Therapeutic compositions of undecylenic acid and arginine

ABSTRACT

Compositions including a complex of fatty acids (e.g., including one or more C4 to C40 fatty acids, such as a C4 to C20 fatty acid) and one or more amino acids (and particularly one or more amino acids having electrically charged basic side chains, e.g., Arginine, Lysine, etc.) for use as an anti-pathogenic composition. These compositions may include the complex of fatty acid:amino acid having a lamellar supramolecular structure. In particular, described herein are therapeutic compositions of undecylenic acid:Arginine forming a complex of undecylenic acid and Arginine.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims priority as a continuation-in-part of PCTApplication No. PCT/US2019/054044, titled “THERAPEUTIC COMPOSITIONS,”filed on Oct. 1, 2019, which claims priority to each of: U.S.Provisional Patent Application No. 62/739,844, titled “ANTI-PATHOGENICTHERAPEUTIC COMPOSITIONS,” filed on Oct. 1, 2018; U.S. ProvisionalPatent Application No. 62/845,858, titled “THERAPEUTIC COMPOSITIONS,”filed on May 9, 2019; and U.S. Provisional Patent Application No.62/845,859, titled “THERAPEUTIC COMPOSITIONS,” filed on May 9, 2019.Each of these applications is herein incorporated by reference in itsentirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD

Compositions of fatty acids (e.g., C4-C40 fatty acids, C4-C20 fattyacids, C8-C20 fatty acids) including but not limited decanoic acid,octanoic acid and undecylenic acid, etc., and amino acids (e.g., aminoacids that have electrically charged basic side chains, including butnot limited to L-arginine and L-lysine) and therapeutic methods of usingthem, e.g., for anti-pathogen (antibacterial, anti-viral, anti-fungal,anti-microbial) and anti-cancer uses.

BACKGROUND

Pathogens, such as bacteria, viruses, or other microorganisms that cancause disease, are increasingly difficult to treat, particularly withthe increasing advent of antibiotic resistant forms of pathogens. TheUnited States Center for Disease Control (CDC) publishes a list ofpathogenic threats, many of which include drug-resistant microorganismsand microorganisms for which no effective drug therapy exists. Forexample, bacterial infections of the skin and underlying tissue presenta significant clinical treatment issue. These types of infectionscommonly involve gram-positive bacteria that colonize on the skin andunderlying tissue and symptoms can range from mild discomfort to death.Bacteria cause a number of skin conditions such as impetigo, cellulitis,boils, and acne. Deep tissue infections of surgical wounds or traumaticwounds can invade the blood stream leading to septicemia and death.

Currently, many skin infections that are caused by gram-positivebacteria are aggressively treated with antibiotics. However, as strainsof pathogenic bacteria develop antibiotic resistance mechanisms, itbecomes crucial to develop novel therapies that inhibit bacterial growthwithout using traditional antibiotics. In recent years, the issue ofbacterial antibiotic resistance has become much more recognized with thedevelopment of so-called ‘superbugs’ such as methicillin-resistantStaphylococcus aureus (MRSA) and vancomycin-resistant enterococcus(VRE). These bacteria are common skin pathogens that have developedsignificant antibiotic resistance. With the continued use of antibioticsin both humans and animals bred for consumption, many common strains ofskin bacteria are developing widespread antibiotic resistance leading toa serious health care issues. Common bacteria that are implicated inskin infections are Methicillin resistant Staphylococcus aureus, S.pyogenes and S. pneumoniae, E. faecalis and S. agalactiae. As thesebacteria colonize the skin they break down the epidermis, induce aninflammatory response, and if untreated, invade into deeper tissuecausing cellulitis. In extreme cases the bacteria invade the circulatorysystem causing sepsis and possible death.

It has become evident to the medical community that novel treatmentsmust be developed to address this issue. However, many pharmaceuticalcompanies have not aggressively pursued the development of new,antimicrobial treatments for skin and wound infections.

The number of people suffering from cancer and multi-resistantinfections has increased in recent years, such that both diseases arealready seen as current and future major causes of death. Moreover,chronic infections are one of the main causes of cancer, due to theinstability in the immune system that allows cancer cells toproliferate. Likewise, the physical debility associated with cancer orwith anticancer therapy itself often paves the way for opportunisticinfections. It is urgent to develop new therapeutic methods, with higherefficacy and lower side-effects. In particular, it would be beneficialto provide anti-pathogenic agents that may also have anti-cancerbenefits.

Described herein are compounds and methods of using them to treat anumber of pathogens, including both gram-negative and gram-positivebacteria, fungi and viruses. These compounds may also be useful to treatcancer, and methods of treating or preventing cancer are also described.

SUMMARY OF THE DISCLOSURE

The present invention relates to compositions of fatty acids and aminoacids for use as a therapeutic composition. Examples of fatty acidsinclude unsaturated fatty acids (e.g., undecylenic acid (UCA)), andsaturated fatty acids (e.g. lauric acid). Examples of amino acidsinclude aliphatic amino acids (e.g., L-arginine (LARG)), aromatic aminoacids (e.g. Histidine) and imino amino acids (e.g. proline) and aminoacids having electrically charged basic side chains (e.g., Arginine,Histidine, and Lysine). In some variations, the amino acids may have beArginine (e.g., LARG) and/or Lysine. These compositions may be selectedfor relatively high chemical stability, particularly at lowertemperatures, and relatively long shelf-life, along with high-efficacyand high-safety.

Also described herein are therapeutic methods for treating a patientwith these compositions, including for use to treat a communicabledisease, such as an anti-pathogenic composition and/or anti-cancercomposition. Anti-pathogenic may include antimicrobial, antibacterial,antifungal, antiviral, etc. Anti-cancer may include anti-tumor,anti-proliferation, anti-neoplastic etc. These compositions may findparticular use as antibacterial, antiviral and in some variations,anticancer compositions. The composition may be used for topicalapplication. For example, in some variations, they may be applied to theskin (cutaneously) for a local (topical) or body-wide (systemic) effect,including via delivery through the skin by a patch (transdermally) for asystemic effect. In some variations, they may be applied orally, in somevariations, they may be applied by injection (e.g., intravenously,intramuscularly, intrathecally, subcutaneously, etc.). In somevariations, they may be applied sublingually or between the gums andcheek (e.g., buccally). In some variations, they may be applied rectallyor vaginally. In some variations, they may be applied intraocularlyand/or by the optic nerve. In some variations they may be sprayed intothe nose and absorbed through the nasal membranes (nasally) and/orbreathed into the lungs, usually through the mouth (by inhalation) ormouth and nose (by nebulization).

In general, described herein are therapeutic compositions that include afatty acid and an amino acid, and in particular a C4-C20 fatty acid andan amino acid such as an amino acid having an electrically charged basicside chain; for example, described herein are therapeutic compositionsof undecylenic acid and L-Arginine in a ratio within a working range toproduce an anti-pathogenic and/or anti-cancer effect (e.g., having amolar ratio of fatty acid to amino acid of between about 1:0.6 to about1:1.6, e.g., between about 1:0.7 to about 1:1.6). For example, describedherein are therapeutic compositions comprising a mixture of undecylenicacid:L-Arginine in a ratio of between about 1:0.6 to about 1:1.6. Insome variations a therapeutic composition comprises a mixture ofundecylenic acid:L-Arginine in a ratio of between about 1:0.6 to about1:1.6, wherein the therapeutic composition does not include cetylalcohol. The compositions described herein may not include any organicsolvents. In some variations, a therapeutic composition comprises amixture of undecylenic acid:L-Arginine in a ratio of between about 1:0.6to about 1:1, wherein the concentration of L-Arginine is between 0.01mg/mL and 182 mg/mL.

The ratio of undecylenic acid:L-Arginine may be between 1:0.6 to about1:1. In some variations the ratio of fatty acid to amino acid (e.g.,undecylenic acid:L-Arginine) is in an approximately 1:1 molar ratio. Inother variations the ratio of fatty acid to amino acid (e.g.,undecylenic acid:L-Arginine) is in an approximately 5:4 molar ratio. Anyof these compositions may be an aqueous composition. The pH of thecomposition may be, e.g., between about 6 and about 10; in somevariations the pH is between about 6.9 and about 7.8.

The fatty acids and amino acids described herein may form complexes offatty acids and amino acids. Any of the compositions of fatty acids andamino acids described herein may be referred to as compositionscomprising a complex of fatty acid and amino acid (which may also bereferred to as a fatty acid/amino acid complex), such as a complex toUCA and LARG, etc.).

In variations in which the amino acid is L-Arginine, the concentrationof L-Arginine (LARG) may be less than the solubility limit of LARG. Forexample, the concentration of L-Arginine may be about 182 mg/mL or less.In any of these variations, the concentration of L-Arginine may bebetween about 0.01 mg/mL and about 182 mg/mL. Similarly, the compositionof any other additional or alternative amino acid (e.g., Lysine,Histidine, etc.) may be less than the solubility limit of that aminoacid.

In general, the composition may include an excipient, diluent, orcarrier (in some variations excluding cetyl alcohol). The excipient,diluent, or carrier may be configured for topical application. In somevariations, the excipient, diluent, or carrier may comprise anemulsifying agent. Any of these compositions may include a cooling orheating additive.

The composition may be configured as a liquid or emulsion in a formsuitable for topical administration to a human. For example, thecomposition may be configured for one or more of: oral, parenteral,intraperitoneal, transmucosal, transdermal, rectal, inhalable, andtopical administration. The composition may be configured for coating amedical device.

Also described herein are methods of treating a patient for one or moreof: an infection (e.g., a pathogen, such as a bacteria, yeast, virus,etc.) and/or a cancer. For example, a method of treating a patient todestroy a pathogen may include: administering to said patient atherapeutically effective amount of the anti-pathogenic composition, theanti-pathogenic composition comprising a mixture of fatty acid (e.g., aC4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19or C20 fatty acid) and amino acid (e.g., L-Arginine, Lysine, Histidine,etc.), such as but not limited to undecylenic acid:L-Arginine, in aratio of between about 1:0.6 to about 1:1.6.

In some variations a method of treating a patient to destroy a pathogenusing an anti-pathogenic composition may include: administering to saidpatient a therapeutically effective amount of the anti-pathogeniccomposition, the anti-pathogenic composition comprising a mixture offatty acid (e.g., a C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14,C15, C16, C17 C18, C19, or C20 fatty acid) and amino acid (e.g.,L-Arginine, Lysine, Histidine, etc.), such as but not limited toundecylenic acid:L-Arginine, in a ratio of between about 1:0.6 to about1:1.6, wherein the therapeutic composition does not include cetylalcohol.

A method of treating a patient to destroy a pathogen using ananti-pathogenic composition may include: administering to said patient atherapeutically effective amount of the anti-pathogenic composition, theanti-pathogenic composition comprising a mixture of fatty acid (e.g., aC4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19or C20 fatty acid) and amino acid (e.g., L-Arginine, Lysine, Histidine,etc.), such as but not limited to undecylenic acid:L-Arginine, in aratio of between about 1:0.6 to about 1:1.6, wherein the concentrationof amino acid (e.g., L-Arginine) is between 0.01 mg/mL and 182 mg/mL.

Also described herein are cancer treatment methods, including:administering to a patient in need thereof (e.g., a patient havingcancer), a therapeutically effective amount of a composition comprisinga mixture of fatty acid (e.g., a C4, C5, C6, C7, C8, C9, C10, C11, C12,C13, C14, C15, C16, C17, C18, C19 or C20 fatty acid) and amino acid(e.g., L-Arginine, Histidine, Lysine, etc.), such as but not limited toundecylenic acid:L-Arginine, in a ratio of between about 1:0.6 to about1:1. In some variations the concentration of amino acid (e.g.,L-Arginine) is between 0.01 mg/mL and 182 mg/mL.

In any of these methods and compositions, the ratio of fatty acid toamino acid may be an approximately 1:1 or 5:4 molar ratio. This ratio,of approximately 1:0.95 and 1:0.76, respectively, for UCA:LARG by weightmay provide both efficacy and enhanced chemical stability, allowing thefatty acid and amino acid to remain in solution over time, in particularat low temperatures, including at −20 degrees C. for extended periods oftime.

In any of these methods, the anti-pathogenic composition may be anaqueous composition. The pH of the anti-pathogenic composition may bebetween about 6 and about 10; for example, the pH of the anti-pathogeniccomposition may be between about 6.9 and about 7.8.

In any of these methods the concentration of amino acid (e.g.,L-Arginine) in the composition may be 182 mg/mL or less, e.g., theconcentration of amino acid (e.g., L-Arginine) may be between 0.01 mg/mLand 182 mg/mL.

Administering may comprise applying the anti-pathogenic composition tothe patient's skin. In some variations, administering comprises applyingthe anti-pathogenic composition to the patient's wound. In somevariations, administering comprises applying the anti-pathogeniccomposition systemically to the patient. In some variations,administering comprises spraying the anti-pathogenic composition on thepatient. In some variations, administering comprises releasing theanti-pathogenic composition from a medical device. For example,administering may comprise contacting the patient with a surface of amedical device comprising the anti-pathogenic composition.

The composition (e.g., the anti-pathogenic composition, the anti-cancercomposition, etc.) may further comprise an excipient, diluent, orcarrier, excluding cetyl alcohol; said excipient, diluent, or carriermay be configured for topical application. The excipient, diluent, orcarrier may comprise an emulsifying agent.

Any of these compositions (e.g., the anti-pathogenic composition, theanti-cancer composition, etc.) may further comprise a cooling or heatingadditive, and/or may be configured as a liquid or emulsion in a formsuitable for topical administration to a human.

Also described herein are compositions comprising a complex of fattyacid:amino acid in a molar ratio of between about 1:0.6 to about 1:1.6,wherein the complex of fatty acid:amino acid forms a lamellarsupramolecular structure. For example, a composition may be acomposition comprising a complex of fatty acid:amino acid in a molarratio of between about 1:0.6 to about 1:1.6, wherein the complex offatty acid:amino acid forms a lamellar supramolecular structure, furtherwherein the fatty acid is a C4 to C40 fatty acid. A composition maycomprise a composition comprising a complex of fatty acid:amino acid ina molar ratio of between about 1:0.6 to about 1:1.6, wherein the complexof fatty acid:amino acid forms a lamellar supramolecular structure,wherein the fatty acid is a C4 to C20 fatty acid. In some variations thecomposition comprises a complex of fatty acid:amino acid in a molarratio of between about 1:0.6 to about 1:1.6, wherein the complex offatty acid:amino acid forms a lamellar supramolecular structure, whereinthe amino acid is an amino acid having an electrically charged basicside chain. For example, in some variations a composition is acomposition comprising a complex of fatty acid:amino acid in a molarratio of between about 1:0.6 to about 1:1.6, wherein the complex offatty acid:amino acid forms a lamellar supramolecular structure, whereinthe fatty acid is a C4 to C40 fatty acid, and the amino acid is an aminoacid having an electrically charged basic side chain. A composition maycomprise a composition including a complex of fatty acid:amino acid in amolar ratio of between about 1:0.6 to about 1:1.6, wherein at least 50%of the complex of fatty acid:amino acid forms a lamellar supramolecularstructure, wherein the fatty acid is a C4 to C20 fatty acid, and theamino acid is an amino acid having an electrically charged basic sidechain.

In any of these compositions the molar ratio of fatty acid:amino acidmay be between 1:0.8 to about 1:1.2. The molar ratio of fatty acid:aminoacid may be in approximately 1:1 ratio. The composition may be anaqueous composition.

Any of these compositions may include polymyxin B nonapeptide. Forexample, the polymyxin B nonapeptide may be between 0.1 μg/mL and about50 μg/mL.

Any of these compositions may include an excipient, diluent, carrier orfragrance. The excipient, diluent, carrier, or fragrance may beconfigured for topical application or use on surfaces. In somevariations the composition is configured for one or more of: oral,parenteral, intraperitoneal, transmucosal, transdermal, rectal,inhalable, and topical administration.

The fatty acid may be one or more of: undecylenic acid, decanoic acid,octanoic acid, linoleic acid, arachidonic acid, and lauric acid.

Any of these compositions may further comprise benzalkonium chloride.

In any of these compositions and methods of using them, at least 50% ofthe complex of fatty acid:amino acid may form a lamellar supramolecularstructure. Thus, in any of these compositions, the percentage of complexof fatty acid:amino acid may be enriched for the lamellar supramolecularstructure.

Also described herein are methods of destroying a pathogen, the methodcomprising: administering or applying a therapeutically effective amountof an anti-pathogenic composition, the anti-pathogenic compositioncomprising a complex of fatty acid:amino acid in a molar ratio ofbetween about 1:0.6 to about 1:1.6, wherein the complex of fattyacid:amino acid forms a lamellar supramolecular structure.

In some variations administering comprises applying the anti-pathogeniccomposition to the patient's skin. Administering may comprise applyingthe anti-pathogenic composition to a surface. Administering may compriseapplying the anti-pathogenic composition to the patient's wound.Administering may comprise applying the anti-pathogenic compositionsystemically to the patient. Administering may comprise spraying theanti-pathogenic composition onto the patient or onto the surface.

Thus, described herein are compositions of fatty acid:amino acid thatform a therapeutic complex. For example, described herein arecompositions comprising a composition comprising, as an therapeuticcomplex, a mixture of undecylenic acid:Arginine forming a complex ofundecylenic acid and Arginine having a molar ratio of between 1:0.6 to1:1.6.

For example, a composition as described herein may include a compositioncomprising an aqueous solution of a complex of undecylenicacid:L-Arginine as a therapeutic complex and having a molar ratio ofundecylenic acid:L-Arginine of between 1:0.6 to 1:1.6 at a totalconcentration of at least 0.001% w/w, wherein the composition issubstantially free of cetyl alcohol.

The mixture of undecylenic acid:Arginine may comprise a mixture ofundecylenic acid:L-Arginine. The composition may comprise at least0.001% w/w of the complex of undecylenic acid and Arginine. The molarratio of undecylenic acid:Arginine may be between 1:0.6 to 1:1.2. Themolar ratio of undecylenic acid:Arginine may be in an approximately 1:1molar ratio. In particular, the composition may be substantially free ofcetyl alcohol and/or Rhein. The composition may be an aqueouscomposition.

The composition may include an excipient, diluent, carrier or fragrance.The excipient, diluent, carrier or fragrance may generally be suitablefor topical application or for use on surfaces.

The composition may be configured as a liquid, emulsion, solution,ointment or cream in a form suitable for topical administration to ahuman or for use on surfaces. The composition may be configured for oneor more of: oral, parenteral, intraperitoneal, transmucosal,transdermal, rectal, inhalable, and topical administration. Thecomposition may be configured for administration as a hand sanitizer,surface sanitizer or disinfectant.

Any of these compositions may include benzalkonium chloride.

Also described herein are methods of treating a patient in need thereof,the method comprising: administering to said patient a therapeuticallyeffective amount of a composition comprising an aqueous solution of acomplex of undecylenic acid:L-Arginine in a molar ratio of between 1:0.6to 1:1.6 wherein the total concentration of undecylenic acid:L-Argininein the composition is at least 0.001% w/w. The molar ratio ofundecylenic acid:L-Arginine may be in an approximately 1:1 molar ratio.

Administering may comprise applying the composition to the patient'sskin.

The patient may have a disease or condition mediated by a pathogen. Forexample, the pathogen may be one or more of: a gram-negative bacteria, agram-positive bacteria, a fungus, a Mycobacteria, a pneumoniae bacteria,an E. coli bacteria, and a virus. The patient may have a cancer. Forexample, the patient may have a skin cancer, such as one or more of:actinic keratosis, basal cell carcinoma, melanoma, nonmelanoma skincancer, and/or squamous cell carcinoma of the skin.

Also described herein are compositions comprising, as a therapeuticcomplex, a mixture of decanoic acid:Arginine forming a complex ofdecanoic acid and Arginine having a molar ratio of between 1:0.6 to1:1.6. For example, a composition may be a composition comprising anaqueous solution of a complex of decanoic acid:L-Arginine as atherapeutic complex and having a molar ratio of decanoic acid:L-Arginineof between 1:0.6 to 1:1.6 at a total concentration of at least about0.001% w/w, wherein the composition is substantially free of cetylalcohol.

The mixture of decanoic acid:Arginine may comprise a mixture of decanoicacid:L-Arginine. In some variations, the composition comprises at least0.001% w/w of the complex of decanoic acid:Arginine. In some variations,the molar ratio of decanoic acid:Arginine is between 1:0.6 to 1:1.2. Themolar ratio of decanoic acid:Arginine may be in an approximately 1:1molar ratio. The composition may be substantially free of cetyl alcoholand/or Rhein. The composition may be an aqueous composition.

The composition may include an excipient, diluent, carrier or fragrance.The excipient, diluent, carrier or fragrance may generally be suitablefor topical application or for use on surfaces.

The composition may be configured as a liquid, emulsion, solution,ointment or cream in a form suitable for topical administration to ahuman or for use on surfaces. The composition may be configured for oneor more of: oral, parenteral, intraperitoneal, transmucosal,transdermal, rectal, inhalable, and topical administration. Thecomposition may be configured for administration as a hand sanitizer,surface sanitizer or disinfectant.

Any of these compositions may include benzalkonium chloride. Any ofthese compositions may be configured for administration as a handsanitizer, surface sanitizer or disinfectant.

Also described herein are methods of treating a patient to destroy apathogen, the method comprising: administering to said patient atherapeutically effective amount of an anti-pathogenic composition, theanti-pathogenic composition comprising a mixture of decanoicacid:L-Arginine as a therapeutic complex in a molar ratio of betweenabout 1:0.6 to about 1:1.6 wherein the total concentration of decanoicacid:L-Arginine is at least about 0.001% w/w. The molar ratio ofdecanoic acid:L-Arginine may be in an approximately 1:1 molar ratio. Theanti-pathogenic composition may be an aqueous composition.

Administering may comprise applying the anti-pathogenic composition tothe patient's skin. The pathogen may be one or more of: a gram-negativebacteria, a gram-positive bacteria, a fungus, a Mycobacteria, apneumoniae bacteria, an E. coli bacteria, and a virus.

A method of treating a surface to destroy a pathogen may include:applying to said surface an effective amount of a composition sufficientto kill, inactivate or inhibit the pathogen, the composition comprisinga mixture of decanoic acid:L-Arginine as an active complex in a molarratio of between about 1:0.6 to about 1:1.6 wherein the totalconcentration of decanoic acid:L-Arginine is at least about 0.001% w/w.The molar ratio of decanoic acid:L-Arginine may be in an approximately1:1 molar ratio. Administering may comprise applying the composition todisinfect, clean or sanitize a surface.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 is a graph showing the antibacterial effect of differentcompositions including LARG and UCA.

FIGS. 2A-2B are graphs showing the inhibitory effect of cetyl alcohol(CA) on the ability of compositions of LARG and UCA to prevent bacterialgrowth.

FIG. 3 is a table (Table 1) showing UCA:LARG solubility with LARG abovesolubility limit.

FIG. 4 is a table (Table 2) showing UCA:LARG solubility with LARG belowsolubility limit.

FIG. 5 is a graph showing the bactericidal effect of various ratios ofUCA:LARG on three MRSA isolates.

FIG. 6 is a graph showing the bactericidal effect of various ratios ofUCA:LARG on three MRSA isolates at a finer scale than FIG. 5.

FIG. 7 is a graph showing the bactericidal effect of various ratios ofUCA:LARG on three MRSA isolates at a finer scale than FIGS. 5 and 6.

FIGS. 8-11 show the average bacterial concentration taken from threeMRSA isolates (MRSA 10, 11 and 12) as a function of the UCA:LARG ratio.The y-axis (bacterial concentration, in CFU/mL) in FIG. 8 extends,logarithmically, to a concentration of 140,000,000 (1.4×10⁸) CFU/mL.FIG. 9 shows the same data as FIG. 8, but with a y-axis that extends to1,000,000 (1.0×10⁶) CFU/mL. FIG. 10 shows the same data on a y-axis thatextends to 100,000 (1.0×10⁵) CFU/mL. FIG. 11 shows the same data on ay-axis that extends to 30,000 (3.0×10⁴) CFU/mL.

FIG. 12 is a graph showing the pH of various compositions includingdifferent UCA:LARG ratios in water.

FIG. 13 is a graph showing the in vitro efficacy of one variation of acompound as described herein (referred to as “GS-1”) against eightisolates of methicillin-resistant Staphylococcus aureus (MRSA) at a drugdilution of 1:16. MRSA is gram-positive.

FIG. 14 is a graph illustrating the efficacy of the GS-1 compoundagainst two isolates of Escherichia coli (EC) at a drug dilution of1:16. EC is gram-negative.

FIG. 15 is an example of a graph illustrating the in vitro efficacy ofGS-1 against three isolates of CRE-positive Klebsiella pneumoniae(KPCRE) at a drug dilution of 1:16. KPCRE is gram-negative.

FIG. 16 illustrates the in vitro efficacy of GS-1 against two isolatesof Pseudomonas aeruginosa (PSA) at a drug dilution of 1:8. PSA isgram-negative.

FIG. 17 shows the in vitro efficacy of GS-1 against C6 rat glioma cancercells as a function of drug dilution.

FIGS. 18A-18E illustrate microscopic imaging of in vitro efficacy forGS-1 against C6 rat glioma cancer cells as a function of drug dilution.FIG. 18A shows treated cells at 1:64 dilution of GS-1, showing thegreatest amount of cell death. FIG. 18B shows cells treated with a 1:128dilution of GS-1. FIG. 18C shows cells treated with a 1:256 dilution ofGS-1. FIG. 18D shows cells treated with a 1:512 dilution of GS-1. FIG.18E shows the untreated control.

FIG. 19 is a table showing the results of a freezer stability study forexemplary compositions as described herein.

FIG. 20 is a graph illustrating the therapeutic effects of fourcompositions of a fatty acid:amino acid at about a 1:0.76 (fattyacid:amino acid) ratio by weight when diluted and used to treat MRSA.GS-1 corresponds to UCA:LARG (at a molar ratio of 1:0.8) as describedabove, at a dilution of 1:128 of an approximately 32% w/w mixture,resulting in a concentration of about 0.25% total active pharmaceuticalingredients (APIs). GS-2 corresponds to a mixture of Decanoic acid:LARG,(having a molar ratio of about 1:0.8) at a dilution of 1:128 of anapproximately 32% w/w mixture, resulting in a concentration of about0.25% w/w total APIs. GS-3 corresponds to a mixture of Octanoicacid:LARG, (having a molar ratio of about 1:0.6) at a dilution of 1:128of an approximately 32% w/w mixture, resulting in a concentration ofabout 0.25% w/w total APIs. GS-4 corresponds to a mixture of Linoleicacid:LARG at a concentration of about 1.64 mg/mL (0.16% w/w) total APIs,having a molar ration of about 1:6.1.

FIG. 21 is a graph showing activity of GS-2 (Decanoic acid:LARG, at aconcentration of about 0.25% w/w total API and a molar ratio of about1:0.8) against MRSA compared to saline-treated control for six clinicalisolates for 24 hours. The Decanoic acid:LARG composition produced abactericidal effect in 100% of the isolates.

FIG. 22 is a graph showing activity of GS-3 (Octanoic acid:LARG, at aconcentration of about 0.25% w/w total API and a molar ratio of about1:0.6) against MRSA compared to saline-treated control for six clinicalisolates for 24 hours. The Octanoic acid:LARG composition produced aninhibitory effect in 66.7% of the isolates and a bacteriostatic effectin 33.3%.

FIG. 23 is a graph showing activity of GS-4 (Linoleic acid:LARG, at aconcentration of about 0.16% w/w total API and a molar ratio of about1:6.1) against MRSA compared to saline-treated control for six clinicalisolates for 24 hours. GS-4 produced a bactericidal effect in 50% of theisolates and an inhibitory effect in 50%.

FIG. 24 is a graph showing activity of GS-5 (UCA:Lysine, at aconcentration of about 0.25% w/w total API and a molar ratio of about1:1.0) against MRSA compared to saline-treated control for five clinicalisolates for 24 hours. GS-5 produced a bactericidal effect in all of theisolates at this concentration.

FIG. 25 is a graph showing activity of GS-6 (UCA:Histidine), at a molarratio of about 1:0.8 (e.g., 5:4). The weight ratio is about 1:0.76. Theuse of Histidine as the amino acid also showed a significant amount ofactivity, as shown. Preliminary results suggest a similar range ofefficacy as seen with UCA:Lysine and UCA:L-Arginine).

FIG. 26 is a table matrix showing the results of testing a variety ofamino acid and fatty acid combinations. Exemplary C4-C20 fatty acids arelisted in the column, while amino acids (grouped by characteristics) areshown along the top. Negative results and positive results are indicatedin the corresponding boxes, where negative results indicate a failure toform a solution and/or to have significant anti-pathogenic/anti-cancereffect. Positive results indicated that the combination of amino acidand fatty acid formed a therapeutic composition, e.g., in a molar ratioof fatty acid:amino acid of between about 1:0.6 to about 1:1.6. Questionmarks, (−) and (+) indicate preliminary testing, while “Yes” or “No”indicated confirmed data.

FIG. 27 is a graph showing anti-cancer efficacy of the therapeuticcomposition of an agent comprising a mixture of fatty acid and aminoacid as described herein, in which the molar ratio of fatty acid:aminoacid is between about 1:0.6 and about 1:1.6; in this example, the agentis a solution of GS-1 (LARG and UCA) tested against human cancer cells,showing a working drug concentration of 0.3% w/w.

FIG. 28 is a graph showing the anti-cancer effect of an example of themixture of fatty acid and amino acid as described herein, in which themolar ratio of fatty acid:amino acid is between about 1:0.6 and about1:1.6 (in this example, LARG and UCA, GS-1) at different concentrationson cultured PC3 human prostate cancer cells following a 24 hourincubation with various concentrations of the agent.

FIG. 29 is a graph showing the anti-cancer effect of an example of themixture of fatty acid and amino acid as described herein, in which themolar ratio of fatty acid:amino acid is between about 1:0.6 and about1:1.6 (in this example, LARG and UCA, GS-1) at different concentrationson cultured MCF7 breast cancer cells following a 24 hour incubation withvarious concentrations of the agent.

FIG. 30 is a graph showing the anti-cancer effect of an example of themixture of fatty acid and amino acid as described herein, in which themolar ratio of fatty acid:amino acid is between about 1:0.6 and about1:1.6 (in this example, LARG and UCA, GS-1) at different concentrationson cultured MM170 human melanoma cancer cells following a 24 hourincubation with various concentrations of the agent.

FIG. 31 is a graph showing the anti-cancer effect of an example of themixture of fatty acid and amino acid as described herein, in which themolar ratio of fatty acid:amino acid is between about 1:0.6 and about1:1.6 (in this example, LARG and UCA, GS-1) at different concentrationson cultured U937 human leukemia cancer cells following a 24 hourincubation with various concentrations of the agent.

FIG. 32 is a graph showing the anti-cancer effect of an example of themixture of fatty acid and amino acid as described herein, in which themolar ratio of fatty acid:amino acid is between about 1:0.6 and about1:1.6 (in this example, LARG and UCA, GS-1) at different concentrationson cultured A549 human lung cancer cells following a 24 hour incubationwith various concentrations of the agent.

FIG. 33 is a graph showing anti-cancer test results for another exampleof a mixture of fatty acid and amino acid as described herein, in whichthe molar ratio of fatty acid:amino acid is between about 1:0.6 andabout 1:1.6 (in this example, LARG and Decanoic acid, GS-2) at differentconcentrations on cultured A549 human lung cancer cells following a 24hour incubation with various concentrations of the agent.

FIG. 34 is a graph illustrating the in vitro anti-viral activity of anexample of a therapeutic composition of fatty acid and amino acid asdescribed herein, in which the molar ratio of fatty acid:amino acid isbetween about 1:0.6 and about 1:1.6 (in this example, LARG and UCA,GS-1) against Herpes simplex viruses (HSV) infected cells at variousconcentrations.

FIG. 35 is a graph illustrating the in vitro anti-viral activity of anexample of a therapeutic composition of fatty acid and amino acid asdescribed herein, in which the molar ratio of fatty acid:amino acid isbetween about 1:0.6 and about 1:1.6 (in this example, LARG and UCA,GS-1) against pseudo-Ebola infected cells at various concentrations.

FIG. 36 is a table summarizing the minimum bactericidal concentrationsfor examples of various compositions of a complex of fatty acid andamino acid as described herein (e.g., GS-9, GS-10, GS-11, GS-12, andGS-13) against various types of bacteria.

FIG. 37 is a table summarizing the EC₅₀ data for one example of acomposition of a complex of fatty acid and amino acid as describedherein (GS-12, at an approximately 1:1 molar ratio of Linoleicacid:Lysine) against various viruses, including Human Rhinovirus-14,SARS Coronavirus, Dengue virus and Yellow Fever virus.

FIG. 38 is a table summarizing the IC₅₀ data for examples of GS-9 orGS-12 against various cancer cell types. These results arerepresentative of other composition of complexes of fatty acid and aminoacid as described herein.

FIG. 39A is a graph showing the low cytotoxicity of one example of atherapeutic composition of fatty acid and amino acid as described herein(in this example, an aqueous solution of GS-1, Undecylenicacid:Arginine, in a 1:1 molar ratio) against a normal cell line (Verocells).

FIG. 39B is a graph showing the cytotoxicity of the therapeuticcomposition of fatty acid and amino acid (e.g., GS-1, in a 1:1 molarratio) against human leukemia cells after a brief exposure.

FIGS. 40A-40C are transmission electron microscopy (TEM) images of oneexample of a therapeutic composition of fatty acid and amino acid asdescribed herein at increasing concentration (FIG. 40A shows 10 μg/mL ofGS-9, e.g., Arachidonic acid:Lysine, in a 1:1 molar ratio; FIG. 40Bshows 100 μg/mL of GS-9; FIG. 40C shows 1000 μg/mL of GS-9), showing alamellar supramolecular structure.

FIG. 41 is another example of the therapeutic composition of fatty acidand amino acid (in this example, GS-9, in a 1:1 molar ratio) shown inFIG. 40, self-assembling into lamellar supramolecular structures fromelongated string-like structures. FIG. 41 shows GS-9 at 1 μg/mL).

FIG. 42 is a TEM image showing a lamellar supramolecular structure of atherapeutic composition of fatty acid and amino acid (in this example,GS-1, Arginine and UCA, in a 1:1 molar ratio).

FIG. 43A is an example of a TEM image showing the supramolecularstructure of an example of a therapeutic composition of a fatty acid andan amino acid (e.g., GS-1, in a 1:1 molar ratio). FIG. 43B shows ahigher-magnification view of the TEM image of FIG. 43A, showing thelamellar supramolecular structure.

FIGS. 44A-44D show other examples of TEM images of GS-1 (in a 1:1 molarratio), similar to that shown in FIGS. 43A-43B, showing thesupramolecular structure.

DETAILED DESCRIPTION

In general, described herein are therapeutic compositions (e.g.,anti-pathogenic and/or anti-cancer compositions) that include both afatty acid (e.g., one or more of a C4, C5, C6, C7, C8, C9, C10, C11,C12, C13, C14, C15, C16, C17, C18, C19, or C20 fatty acid, etc., such asone or more of undecylenic acid (UCA), decanoic acid, octanoic acid,linoleic acid, arachidonic acid, lauric acid, etc.) and an amino acid(e.g., one or more of: arginine, Lysine, Histidine, etc.) in which theratio of the total fatty acid to the total amino acid is within a rangeof about 1:0.60 to about 1:1.6 (e.g., between about 1:0.6 and 1:1.2,between about 1:0.8 and 1:1.2, about 1:1, etc.). In some variations theArginine is L-Arginine (LARG). The concentration of the amino acid inthe composition may be less than the solubility limit of the amino acid.In some variations, the composition may include a ratio of fatty acid toamino acid (e.g., UCA:ARG; UCA:LARG, decanoic acid:ARG, Decanoicacid:LARG; Octanoic acid:ARG; Octanoic:LARG, etc.) that is approximatelya 1:1 molar ratio (e.g., between about 1:0.95 by weight and about 0.95:1by weight). In some variations, the composition may include a ratio offatty acid to amino acid (e.g., UCA:LARG ratio) that is approximately a5:4 molar ratio (e.g., about 1:0.76 by weight). These compositions mayhave enhanced stability and efficacy, including over extended periods oftime at −20° C. or less.

Compositions outside of this range are much less effective, orineffective, and/or may be unstable. For example, PCT/US2018/018077,filed on Feb. 13, 2018 (titled “ANTI-PATHOGENIC THERAPEUTICCOMPOSITIONS”), herein incorporated by reference in its entirety and US2015/0366925, filed on Jan. 27, 2014 (as PCT application no.PCT/US14/13120) describes antibacterial compositions of Chinese rhubarbextract, and in particular, compositions including an active ingredientof Chinese rhubarb extract, Rhein. These compositions typically includedL-arginine (LARG) and undecylenic acid (UCA) as accessory molecules incompositions including other materials for treatment as an antimicrobialmaterial; LARG and UCA were shown to have no effect on bacterial growthwithout the addition of Chinese rhubarb extract/Rhein (see, for example,FIGS. 4-7 of US 2015/0366925). This previous work described drugproducts that included a combination of L-arginine, undecylenic acid,Chinese rhubarb/Rhein, and cetyl alcohol (as an excipient) in water.Based on these initial findings, at least all of the three components,LARG, UCA and Chinese rhubarb extract/Rhein, were believed to berequired in order to achieve a robust therapeutic effect. This workfurther taught that cetyl alcohol was needed to get these componentsinto solution together. It was therefore believed that the highestefficacy would occur at the maximum achievable concentration of allthree components (individually and collectively). As a result, LARG wasalways included at above its solubility limit (e.g., super-saturated).

Surprisingly, the inventors have developed a composition in which just afatty acid, such as, but not limited to, UCA, and an amino acid, such asARG (e.g., LARG), may together form a remarkably effectiveanti-pathogenic and anti-cancer composition when Chinese rhubarb extract(including Rhein) is absent from the composition. Thus, described hereinare compositions in which the active ingredient is formed as a complexof just the fatty acid and an amino acid (and in particular a complex ofa fatty acid and one or more of Arginine, Histidine and/or Lysine). Inparticular, described herein are compositions of virtually any C4-C40(e.g., C4-C20, C8-C20, C8-C18, C4-C18) fatty acid with certain aminoacids (e.g., Arginine, Histidine, Lysine), including but not limited toUCA and LARG, within a defined range of concentrations that havesuperior stability in solution as well as efficacy as anti-pathogenicand/or anti-cancer therapies. Further, any of these compositions,including compositions of UCA and LARG, may be made without cetylalcohol or other similar excipients, previously thought to be necessaryfor solubility of the fatty acid and amino acid (e.g., to keep UCA andLARG in solution together). Surprisingly, excipients such as cetylalcohol significantly inhibit the efficacy of the fatty acid and aminoacid (e.g., UCA and LARG) compositions. For example, the highestefficacy of an UCA/LARG composition occurs at concentrations of UCA andLARG that are well below the maximum achievable concentration of allthree components, and in particular, occur at concentrations of LARGbelow its native solubility limit. As described herein, compositions offatty acids and amino acids (e.g., UCA/LARG) have significant efficacy(e.g., anti-pathogenic and/or anti-cancer efficacy) only within aspecified window of UCA:LARG concentration ratios, which can only beachieved when LARG is at or below its native solubility limit (and inthe absence of Chinese rhubarb extract/Rhein and/or cetyl alcohol).Further, this optimal range (e.g., ratios of UCA to LARG of 1 to about1, such as between about 1:0.6 to 1:1.6, e.g., between about 1:0.8 to1:1.2, about 1:1, etc.) is tightly circumscribed: at one end of thewindow (e.g., above about 1:1.6) there is sharp drop off in efficacy. Atthe other end of the window of optimal range there is a solubility dropoff, where the fatty acid (e.g., UCA) solubility drops off very sharply.Inside the window, efficacy is far greater than previously observed, andthere is a strong trend towards an optimum value.

Furthermore, as will be described in greater detail herein, it may beparticularly beneficial to form complexes of the fatty acid (e.g., aC4-C40 fatty acid, a C4-C20 fatty acid, C8-C20 fatty acid, C8-C18 fattyacid, C4-C18 fatty acid) with certain amino acids (e.g., Arginine,Histidine, and/or Lysine) in which the complexes form a multi-layered(e.g., lamellar) supramolecular structure. Without being bound bytheory, these supramolecular structures may assist in destroyingpathogens with some specificity, including viruses and bacteria.Further, these lamellar structures may package additional activeingredients, including agents having limited water solubility, withinthe supramolecular structure, and may also assist with drug deliveryacross or through tissue (e.g. skin absorption) or into cells.

For convenience herein, compositions of particular fatty acids and aminoacids known to form complexes (including supramolecular structures) maybe referred to herein in shorthand such as: GS-1 (Undecylenicacid:Arginine, e.g., Undecylenic acid:L-Arginine); GS-2 (Decanoicacid:Arginine, e.g., Decanoic acid:L-Arginine); GS-3 (Octanoicacid:Arginine, e.g., Octanoic acid:L-Arginine); GS-4 (Linoleicacid:Arginine, e.g., Linoleic acid:L-Arginine); GS-5 (Undecylenicacid:Lysine); GS-6 (Undecylenic acid:Histidine); GS-7 (Decanoicacid:Lysine); GS-8 (Arachidonic acid:Arginine); GS-9 (Arachidonicacid:Lysine); GS-10 (Lauric acid:Arginine, e.g., Lauricacid:L-Arginine); GS-11 (Lauric acid:Lysine); GS-12 (Linoleicacid:Lysine); GS-13 (Lauric acid:Lysine).

As mentioned above, prior compositions of UCA and LARG for use as anantimicrobial included both Chinese rhubarb/Rhein and cetyl alcohol(CA), and the Chinese Rhubarb extract (Rhein) and cetyl alcohol wereboth believed to be necessary. Surprisingly, the inventors have foundthat removing both Chinese rhubarb/Rhein and CA dramatically improvedthe activity of the resulting compound; this improvement was even moreprofound when the ratio of the UCA:LARG was adjusted to be between about1:0.6 and 1:1.6. This was unexpected, as Rhein has antimicrobialactivity and CA is a widely accepted excipient (and hence should notaffect efficacy).

For example, FIG. 1 shows the antimicrobial effect of variouscompositions including UCA and LARG against three MRSA isolates. In FIG.1, one exemplary composition, “WT13-13” contains UCA, LARG, Rhein, CAand water; the composition of UCA+LARG+CA contains no Rhein (withwater); and the composition of UCA+LARG contains no Rhein and no CA(with water). In all cases the UCA and LARG concentrations were heldconstant. Note that efficacy is reported in terms of the viablebacterial concentration (in CFU/mL) remaining after 24 hours oftreatment with the drug product (in compliance with CLSI guidelines). Inthis first example, the composition including just UCA and LARG was morestrongly antimicrobial than compositions including Chinese rhubarbextract/Rhein, UCA and LARG, or even UCA and LARG with the excipient,CA. In FIG. 1, the ratio of UCA and LARG is un-optimized.

The UCA+LARG and excipient (e.g., CA) compound was further tested byvarying the concentration of CA and testing antimicrobial efficacy.FIGS. 2A-2B show the resulting efficacy (average taken across three MRSAisolates). FIG. 2A shows a full scale on the y-axis (e.g., up to 8×10⁶CFU/mL), and FIG. 2B shows a zoomed-in y-axis that better illustratesthe low CA concentration behavior. Efficacy is reported in terms of theviable bacterial concentration (in CFU/mL) remaining after 24 hours oftreatment. As shown, increasing amounts of CA in the UCA and LARGcomposition resulted in a decrease in efficacy.

Thus, removing Chinese rhubarb/Rhein and CA resulted in better efficacy.Furthermore, CA imparted a clear inhibitory effect as a function of itsconcentration. These findings conflict with the previously publisheddata showing that UCA and LARG alone (or in combination) did not showsignificant anti-microbial (e.g., antibacterial) effect. See, e.g.,FIGS. 4-7 of US 2015/0366925.

In particular, previously described compositions of UCA and LARGincluded tightly controlled UCA and LARG concentrations. For example, atfull strength, the concentration of LARG was 293 mg/mL and UCA was 180mg/mL, resulting in a UCA:LARG ratio of 1:1.62. That solubility limit ofLARG is 182 mg/mL. The higher ratio of LARG to UCA in these compositionswith Chinese rhubarb extract/Rhein was believed to enhance the efficacyof the Chinese Rhubarb, including assisting in maintaining theextract/Rhein in solution.

Initial experiments began by varying the ratio of LARG and UCA. Forexample, as shown in FIG. 3 (Table 1), LARG was held at 293 mg/mL, andthe concentration of UCA was varied up and down in increments of 10%.FIG. 3 summarizes the effect of these changes on the solubility of UCAand/or LARG, showing that the UCA:LARG ratio needs to be tightlycontrolled to achieve solubility of both ingredients.

It was previously believed that LARG should be maintained in excess, andin particular, at concentrations above its solubility (e.g.,supersaturated, such as at 293 mg/mL) in order to maintain the activityand/or solubility of the presumed active ingredient, Chinese Rhubarbextract/Rhein. However, as described herein, reducing the LARGconcentration below its solubility limit resulted in a much wider rangeof UCA:LARG ratios that can be achieved and, in particular, including,e.g., ratios of 1:1 and below (i.e. where there is more UCA than LARG byweight), lower ratios have a higher therapeutic efficacy without the useof Chinese Rhubarb extract/Rhein. For example, FIG. 4 (showing table 2)summarizes the solubility results, showing compositions in which LARGconcentration was below the solubility limit of LARG (e.g., 182 mg/mL),and various ratios of UCA:LARG were examined.

It is evident from FIG. 4 that there exists a solubility “ledge”,whereby UCA becomes insoluble between UCA:LARG ratios of 1:0.67 and1:0.64. A very tight range was observed. The actual concentrations ofUCA and LARG differ by 2 mg/mL (e.g., 1.9% and 2.9%, respectively)between these two points.

Thus, while it is possible to formulate a wider range of UCA:LARGconcentrations with LARG below its solubility limit (as opposed to whenit is above its limit), only a subset of these ratios has therapeuticefficacy. A number of UCA:LARG ratios were tested across the fullsolubility range (e.g., between 1:2.00 and 1:0.67) against bacteria. Inall cases, the drug products comprised UCA, LARG and sterile water (bothRhein and CA were excluded), and the total percentage of activeingredients was held constant at 17% by adjusting the water content.FIGS. 5-7 and 8-11 summarize the results of these efficacy tests. Forexample, FIG. 5 shows an example of compositions of UCA and LARG(without Rhein or CA) applied at different ratios of UCA:LARG, showing adramatic antimicrobial effect at ratios of about 1:1.6 (e.g., about1:<1.5). In FIG. 5, the y-axis shows the full scale (up to 1.5×10⁸CFU/mL), while FIGS. 6 and 7 provide zoomed y-axes to better show thechange in efficacy that is strongly dependent on the ratio of UCA:LARG.Note that efficacy is reported in terms of the viable bacterialconcentration (in CFU/mL) remaining after 24 hours of treatment with thedrug product (in compliance with CLSI guidelines). Drug dilution inthese examples was 1:16 from 17% active throughout in FIG. 5, FIG. 6,and FIG. 7.

As mentioned, previously described drug products contained LARG aboveits solubility limit and, as such, carried greater than 1:1 UCA:LARGratios (e.g., typically greater than 1:1.6). For example, the previouslydescribed compound including Rhein, WT13, had a UCA:LARG ratio of1:1.62, which is outside of the effective therapeutic range (e.g.,within the “ledge” region in which therapeutic activity falls offdramatically). Dropping the UCA:LARG ratio down dramatically improvedthe efficacy. For example, a UCA:LARG ratio of 1:0.67 is over 50,000×more efficacious than a ratio of 1:1.62 (which is the ratio used in thepreviously described drug product with LARG super-saturated).

To further investigate the efficacy behavior at UCA:LARG ratios belowabout 1:1 (where the above graphs have bacterial concentrations ofzero), the above experiments were repeated with a higher drug dilutionof 1:64 from 17% active. FIGS. 8-11 show the average bacterialconcentration taken from three MRSA isolates (MRSA 10, 11 and 12) as afunction of the UCA:LARG ratio. FIG. 8 shows a full scale on horizontaland vertical axes, while FIG. 9 and FIG. 10 show zoomed vertical axes,and FIG. 11 provides zoomed vertical and horizontal axes. Based on thisdata, a UCA:LARG ratio of about 1:1 or less (e.g., 1:<1) is superior togreater than 1:1 (e.g., 1:>1). As described in greater detail herein, anoptimum activity window of UCA:LARG ratios may be present, e.g.,generally ratios in which for every mass unit of UCA, there is 1.5 massunits or less of LARG. More particularly, for every mass unit of UCA,there is 1.4 mass units or less of LARG, 1.3 mass units or less of LARG,1.2 mass units or less of LARG, 1.1 mass units or less of LARG, 1.0 massunits or less of LARG, etc. For example, the range of ratios of UCA:LARGmay be between about 0.65 mass units of LARG and about 1.5 mass units ofLARG per mass unit of UCA (e.g., UCA:LARG ratio of between 1:0.6 and1:1.6).

In further support of this optimum window, pH tests were performed onvarious compounds of UCA:LARG and a correlation that indicates anoptimum concentration relationship between UCA and LARG was identified.FIG. 12 shows the pH as a function of the UCA:LARG ratio. In thisexample, at ratios above about 1:0.80 the pH rises sharply, which may bedue to a relative abundance of LARG as compared to UCA (LARG is highlybasic). High pH in a drug composition may present a risk of skinirritation in some patients, and can also be difficult for the body tobuffer for systemic applications. The more neutral pH of the optimumratio (e.g., 1:1.0 or less, e.g., 1:<1) may be desirable.

At the previously described UCA:LARG ratio of 1:1.62, cetyl alcohol (CA)and Rhein were able to be placed into solution readily, and oftenoff-gassing of ammonia (released from LARG) was detected. In contrast,at the optimized ratio range (e.g., between 1:0.6 and 1:1.6, e.g.,between about 1:0.7 and 1:1.6) neither CA nor any Rhein may be readilyput or maintained in solution (and ammonia off-gassing has not beendetected).

Thus, described herein are pharmaceutically effective compositionshaving a range of UCA:LARG molar ratios within an effective range ofbetween about 1:0.6 to about 1:1.6. The lower end (e.g., 1:0.6) may belower, e.g., 1: <0.65, if, for example, UCA is made soluble. Thesecompositions may explicitly exclude CA, however any other excipient orbuffer may be used. The range may be, for example, between about 1:0.6(or about 1:0.65, about 1:0.66, about 1:0.67, about 1:0.68, about1:0.69, about 1:0.7, about 1:0.72, etc.) to about 1:1.6 (e.g., about1:1.55, about 1:1.5, about 1:1.45, about 1:1.4, about 1:1.35, about1:1.30, about 1:1.25, about 1:1.20, about 1:1.15, about 1:1.10 about1:1.05, about 1:1.0, about 1:0.9, etc.), including any sub-rangestherein (e.g., 1:0.8 to 1:1.2, about 1:1, etc.).

Also described herein are compositions of UCA and Arginine (e.g., L-Arg)substitutes, by other, similar chemicals in their respective families.

For example, described herein are compositions of fatty acids and aminoacids within a range of molar ratios of about 1:0.6 and 1:1.6, e.g.,fatty acid:amino acid ratios of between about 1:0.6 and 1:1.6 (e.g.,between about 1:0.7 to about 1:1.6, in some variations, having a molarratio of fatty acid to amino acid of about 1:1 or about 5:4). Ingeneral, the fatty acid may be an unsaturated fatty acid (such as, butnot limited to, UCA and linoleic acid, etc.) or a saturated fatty acid(such as, but not limited to, lauric acid, octanoic acid, decanoic acid,etc.). The amino acid may be an amino acid having an electricallycharged basic side chain (such as, but not limited to, LARG, Lysine,etc.), or an aromatic amino acid (such as, but not limited to,Histidine), or an imino amino acid (such as, but not limited to,proline). Surprisingly, outside of these defined molar ranges theanti-pathogenic activity is significantly lost. The range may be, forexample, between about 1:0.6 (or about 1:0.62, about 1:0.63, about1:0.64, about 1:0.65, about 1:0.66, about 1:0.67, about 1:0.68, about1:0.69, about 1:0.7, about 1:0.72, etc.) to about 1:1.5 (or about1:1.45, about 1:1.4, about 1:1.35, about 1:1.30, about 1:1.25, about1:1.20, about 1:1.15, about 1:1.10 about 1:1.05, etc.), including anysub-ranges therein.

The compositions described herein may include one or more other APIs orexcipients. These compositions may be used across a wide range ofapplications/purposes including anti-bacterial, anti-viral, anti-fungal,anti-cancer, with a wide range of delivery routes including skin,systemic, oral, inhaled, intravenous and intramuscular. In particular,the compositions described herein show potent efficacy against bothgram-positive and gram-negative bacteria. The anti-pathogenic compoundsdescribed herein (which may also be referred to herein asanti-pathogenic agents) are effective against a broad variety ofpathogens including in particular gram-negative and gram-positivebacteria, fungi and viruses. These compositions may also be effectiveagainst other classes of bacteria, including mycobacterium, as well asagainst fungi.

These anti-pathogenic compounds may be used to treat or preventinfections, including bacterial infections, in, e.g., a human ornon-human patient. A method of treatment of infection may be separatefrom a method of prevention. These anti-pathogenic compounds may be usedto kill, stop or slow the progression of a pathogenic infection (or tokill and/or slow or stop the growth of a pathogen in or on a body ormaterial, such as a surface). For example, described herein arebacteriostatic compositions. For example, described herein arebacteriostatic compositions that include a mixture of between 1:0.6 to1:1.6 fatty acid:amino acid (e.g., UCA:LARG); additional materials(excipient, diluent, or carrier) may be combined with the mixture toform the anti-pathogenic compound. In some variations, the amino acidincludes L-arginine, the fatty acid includes undecylenic acid.

For example, in some variations, a method of treatment does not includeprophylaxis. For example, a method of treating an infection may includea method of reducing a pathogen in or on a body by x % (where x is 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, etc.) or more over a period oftime (e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12hours, 24 hours, 36 hours, etc.). For example, a method of treatment mayinclude a method of reducing a viral load by x % (where x is 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95%, etc.) or more over a period of time(e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24hours, 36 hours, etc.).

Any of the therapeutic (e.g., anti-pathogenic, anti-cancer) compositionsdescribed herein may be used to treat a patient, e.g., a human ornon-human patient, suffering from or at risk of developing an infectionand/or cancer by administering a therapeutically effective amount of oneor more of the therapeutic compositions described herein including oneor more amino acids and one or more fatty acids in the recited range.For example, described herein are methods of treating a patient, e.g., ahuman or non-human patient, suffering from or at risk of developing aninfection by administering a therapeutically effective amount of acomposition that contains one or more fatty acids and one or more aminoacids in a molar ratio of between about 1:0.6 to 1:1.6. The range maybe, for example, between about 1:0.6 (or about 1:0.66, about 1:0.67,about 1:0.68, about 1:0.69, about 1:0.7, about 1:0.72, etc.) to about1:1.45 (or about 1:1.4, about 1:1.35, about 1:1.30, about 1:1.25, about1:1.20, about 1:1.15, about 1:1.10 about 1:1.05, about 1:1, about 1:9,etc.), including any sub-ranges therein.

Any of the compositions described herein (including the anti-pathogeniccompositions, anti-cancer compositions, sanitizing compositions) may bepart of a kit that includes one or more of the compositions along withinstructions for using or administering the compositions. Thus, thepresent disclosure further provides kits for carrying out the methods ofthe invention, which comprises one or more compositions describedherein. The kits may employ any of the compositions disclosed herein. Inone variation, the kit employs a composition described herein or a saltthereof. The kits may be used for any one or more of the uses describedherein, and, accordingly, may contain instructions for the treatment ofa patient as described herein. Kits generally comprise suitablepackaging. The kits may comprise one or more containers comprising anyof the compositions described herein. The kits may be in unit dosageforms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Forexample, kits may be provided that contain sufficient dosages of acomposition as disclosed herein and/or additional pharmaceuticallyactive compositions useful for a disease detailed herein to provideeffective treatment of an individual for an extended period, such as anyof 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4months, 5 months, 7 months, 8 months, 9 months, or more. Kits may alsoinclude multiple unit doses of the compositions and instructions for useand be packaged in quantities sufficient for storage and use inpharmacies (e.g., hospital pharmacies and compounding pharmacies). Thekits may optionally include a set of instructions, generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable, relatingto the use of composition(s) of the methods of the present invention.The instructions included with the kit generally include information asto the compositions and their administration to an individual.

The one or more amino acids may include, e.g., one or more of: arginine,asparagine, aspartate, glutamate, glutamine, histidine, serine,threonine and lysine. The one or more amino acids may include, e.g., analiphatic amino acid, including one or more of: Alanine, Arginine,Asparagine, Aspartic acid, Cysteine, Glutamine, Glutamic acid, Glycine,Isoleucine, Lysine, Leucine, Methionine, Serine, Threonine, and Valine.In particular, the one or more amino acids may include Arginine,Histidine and/or Lysine. Fatty acids may be saturated or unsaturated(e.g. mono-unsaturated or poly-unsaturated). In particular, the fattyacid may be a fatty acid having a lipid number (e.g., number of carbons)of between C4 and C20, or C4 and C18 (e.g., one or more of: Butanoicacid, Isobutyrate, Pentanoic acid, 3-Methylbutanoate, Hexanoic acid,Heptanoic acid, Octanoic acid, Nonanoic acid, Decanoic acid, Undecanoicacid, Dodecanoic acid, Tridecanoic acid, Tetradecanoic acid,(9Z)-hexadecenoic acid, Hexadecanoic acid, Heptadecanoic acid,Octadecanoic acid, (9Z,12Z)-octadeca-9,12-dienoic acid,(9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid,(6Z,9Z,12Z)-octadeca-6,9,12-trienoic acid,(5E,9E,12E)-octadeca-5,9,12-trienoic acid,(6Z,9Z,12Z,15Z)-octadeca-6,9,12,15-tetraenoic acid, (Z)-octadec-9-enoicacid, (11E)-octadec-11-enoic acid, (E)-octadec-9-enoic acid, etc.). Insome variations, the fatty acid may be an unbranched fatty acid betweenC4 and C18 (e.g., Butanoic acid, Pentanoic acid, Hexanoic acid,Heptanoic acid, Octanoic acid, Nonanoic acid, Decanoic acid, Undecanoicacid, Dodecanoic acid, etc.). For example, an unsaturated fatty acid canbe, e.g., undecylenic acid (e.g., undecanoic acid). In some variations,the fatty acid may include one or more of a C4 to C12 fatty acid (e.g.,Butanoic acid, Isobutyrate, Pentanoic acid, 3-Methylbutanoate, Hexanoicacid, Heptanoic acid, Octanoic acid, Nonanoic acid, Decanoic acid,Undecanoic acid, Dodecanoic acid) or one or more of unbranched C4 to C12fatty acid (e.g., Butanoic acid, Pentanoic acid, Hexanoic acid,Heptanoic acid, Octanoic acid, Nonanoic acid, Decanoic acid, Undecanoicacid, Dodecanoic acid), or C8 to C20 or C8 to C18.

Any of these compositions may include a cooling or heating additive,such as menthol. The compositions may contain a pharmaceuticallyacceptable excipient, diluent, or carrier in addition to the mixture.The amount of excipient, diluent, or carrier does not change therelative ratios (percentages) of the amino acids and fatty acids.

In some variations, a topical formulation does not include anyadditional excipient such as an emulsifying agent. In some variations,the excipient, diluent, or carrier may be configured for topicalapplication. For example, the excipient, diluent, or carrier maycomprise an emulsifying agent. In general, an excipient, diluent orcarrier (including water) is an inactive substance that serves as thevehicle or medium for a drug or other active substance. Excipients mayinclude bulking agents, fillers or the like. The excipient may aid inthe handling of the mixture of active substances by facilitating powderflowability or non-stick properties, aiding in vitro stability (e.g.,prevention of denaturation or aggregation over the expected shelf life),enhancing solubility, improving absorption and/or uptake, providingbetter aesthetic and/or cosmetic features, altering physical propertiesetc.

In general, the compositions (and methods of using them) describedherein may include a complex of the fatty acid and amino acid (e.g., aC4-C40 fatty acid, such as a C8-C20 fatty acid and one or more ofArginine, Lysine and/or Histidine) in which the complex of fattyacid:amino acid is the active complex, also referred to as a therapeuticcomplex. An active complex or a therapeutic complex provides a directtherapeutic benefit and may also improve, enable or enhance thetherapeutic benefit of another component, including enhancing orfacilitating delivery of other components (e.g., other drugs oringredients). For example, these compositions may include the complex ofthe fatty acid:amino acid as described herein (e.g., UCA:LARG,Arachidonic acid:Lysine, Lauric acid:Lysine, Decanoic acid:Arginine,etc.) in which the primary component of the composition is the complexof the fatty acid:amino acid. Any of these compositions may include thefatty acid:amino acid complex having a lamellar supramolecularstructure, as is apparent under TEM. Thus, any of these compositions maybe selected so that the majority of the fatty acid:amino acid complexesin the solution are in a lamellar supramolecular structure. For example,20% or more, 30% or more, 40% or more, 50% or more, 55% or more, 60% ormore, 70% or more, 75% or more, 80% or more 85% or more, etc. of thecomplexed fatty acid:amino acid may be maintained in a lamellarsupramolecular structure. The solution may be treated to enrich for thelamellar supramolecular structure, including formulating at a relativelyhigh concentration (which favors the formation of the lamellarsupramolecular structure) and then diluting the formulation; onceformed, the supramolecular structures may remain until disrupted, e.g.,by an alcohol or other agent, such as cetyl alcohol.

Examples of excipients may include: antiadherents (e.g., magnesiumstearate, etc.); binders (e.g., saccharides and their derivatives:disaccharides, sucrose, lactose; polysaccharides and their derivatives:starches, cellulose or modified cellulose such as microcrystallinecellulose and cellulose derivatives including cellulose ethers such ashydroxypropyl cellulose; sugar alcohols such as xylitol, sorbitol ormannitol; protein: gelatin; synthetic polymers:polyvinylpyrrolidone orPVP, polyethylene glycol or PEG, polyvinylpyrrolidone, starch, sucroseand polyethylene glycol, methyl cellulose); coatings (e.g., celluloseether hydroxypropyl methylcellulose, synthetic polymers, shellac, cornprotein zein or other polysaccharides, gelatin); enterics (fatty acids,waxes, shellac, plastics, and plant fibers); colors (titanium oxide, azodyes, etc.); disintegrants (e.g., crosslinked polymers: crosslinkedpolyvinylpyrrolidone such as crospovidone, crosslinked sodiumcarboxymethyl cellulose or croscarmellose sodium, glycolate, etc.);flavors (fruit extract, etc.); glidants (e.g., fumed silica, talc, andmagnesium carbonate, etc.); lubricants (e.g., talc or silica, and fats,e.g. vegetable stearin, magnesium stearate or stearic acid, etc.);preservatives (e.g., antioxidants like vitamin A, vitamin E, vitamin C,retinyl palmitate, and selenium; cysteine, methionine; citric acid,sodium citrate; parabens: methyl paraben and propyl paraben); sorbents;sweeteners (e.g., sugar); vehicles (petrolatum, dimethyl sulfoxide,mineral oil, etc.); emollient/stiffening agents (Carnauba wax, Cetylalcohol, Cetyl ester wax, Emulsifying wax, Hydrous lanolin, Lanolin,Lanolin alcohols, Microcrystalline wax, Paraffin, Petrolatum,Polyethylene glycol, Stearic acid, Stearyl alcohol, White wax, Yellowwax, etc.); emulsifier/emulsifying agent/solubilizing agent (Polysorbate20, Polysorbate 80, Polysorbate 60, Poloxamer, Emulsifying wax, Sorbitanmonostearate, Sorbitan monooleate, Sodium lauryl sulfate, Propyleneglycol monostearate, Diethylene glycol monoethyl ether, Docusate sodium,etc.); humectant (e.g., Glycerin, Propylene glycol, Polyethylene glycol,Sorbitol solution, 1,2,6 Hexanetriol, etc.); thickening/gelling agent(Carbomer, Methyl cellulose, Sodium carboxyl methyl cellulose,Carrageenan, Colloidal silicon dioxide, Guar gum, Hydroxypropylcellulose, Hydroxypropyl methyl cellulose, Gelatin, Polyethylene oxide,Alginic acid, Sodium alginate, Fumed silica, etc.); preservative(Benzoic acid, Propyl paraben, Methyl paraben, Imidurea, Sorbic acid,Potassium sorbate, Benzalkonium chloride, Phenyl mercuric acetate,Chlorobutanol, Phenoxyethanol, etc.); permeation enhancer (Propyleneglycol, Ethanol, Isopropyl Alcohol, Oleic acid, Polyethylene glycol,etc.); chelating agent (Ethylene diamine tetraacetate, etc.);acidifying/alkalizing/buffering agent (Citric acid, Phosphoric acid,Sodium hydroxide, Monobasic sodium Phosphate, Trolamine, etc.);vehicle/solvent (Purified water, Hexylene glycol, Propylene glycol,Oleyl alcohol, Propylene carbonate, Mineral oil, etc.). These examplesmay be redundant, and different excipients may be used for differentreasons, and may have dual or multiple functionalities.

The composition may be configured as a liquid or emulsion in a formsuitable for topical administration to a human, including a spray,lotion, cream, ointment, tincture, etc.

Also described herein are methods of treating a patient to destroy apathogen using an anti-pathogenic agent effective against gram-negativeand gram-positive bacteria, viruses and fungi. For example, the methodmay include: administering to said patient a therapeutically effectiveamount of the anti-pathogenic agent, the anti-pathogenic agentcomprising a mixture of fatty acid and amino acid as described herein,in which the molar ratio of fatty acid:amino acid is between about 1:0.6and about 1:1.6, and any subrange thereof.

Administering may comprise applying the anti-pathogen agent to thepatient's skin, to the patient's wound, etc. For example, administeringmay comprise spraying the anti-pathogen agent on the patient.Alternatively or additionally, administering may comprise applying theanti-pathogenic agent systemically to the patient. The compositionsdescribed herein may also be used as a coating (e.g., to a medicaldevice, implant, etc.).

These compositions and methods of using them may be used against avariety of pathogens and/or cancers. For example, the compositions andmethods of using them may be used to treat one or more of: agram-negative bacteria, a gram-positive bacteria, a fungus, aMycobacteria, a pneumoniae bacteria, an E. coli bacteria, and/or avirus. This list is exemplary only, and not intended to be exhaustive.Examples of viruses may include: smallpox virus (Variola major andVariola minor), influenza virus (type A, type B, type C, and type D),rubeola virus, mumps virus, rubella virus, varicella zoster virus,hepatitis A virus, hepatitis B virus, Herpes simplex virus 1 and 2,poliovirus, Rabies lyssavirus, Ebola virus, hantaviruses, humanimmunodeficiency virus (HIV), Severe acute respiratory syndrome (SARS)coronavirus, dengue virus, Zika virus, and Epstein-Barr virus.

As mentioned, these compositions may be used to cancer. For example, thecompositions described herein may be used to treat: Adenoid CysticCarcinoma, Adrenal Gland Cancer, Amyloidosis, Anal Cancer,Ataxia-Telangiectasia, Atypical Mole Syndrome, Basal Cell Carcinoma,Bile Duct Cancer, Birt Hogg Dube Syndrome, Bladder Cancer, Bone Cancer,Brain Tumor, Breast Cancer, Carcinoid Tumor, Cervical Cancer, ColorectalCancer, Ductal Carcinoma, Endometrial Cancer, Esophageal Cancer, GastricCancer, Gastrontestinal Stromal Tumor—GIST, HER2-Positive Breast Cancer,Islet Cell Tumor, Juvenile Polyposis Syndrome, Kidney Cancer, LaryngealCancer, Leukemia, Acute Lymphoblastic Leukemia, Acute Lymphocytic (ALL)Leukemia, Acute Myeloid AML Leukemia, Chronic Lymphocytic Leukemia,Chronic Myeloid Leukemia, Liver Cancer, Lobular Carcinoma, Lung Cancer,Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma, Malignant Glioma, Melanoma,Meningioma, Multiple Myeloma, Myelodysplastic Syndrome (MDS),Nasopharyngeal Cancer, Neuroendocrine Tumor, Oral Cancer, Osteosarcoma,Ovarian Cancer, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors,Parathyroid Cancer, Penile Cancer, Peritoneal Cancer, Peutz-JeghersSyndrome, Pituitary Gland Tumor, Polycythemia Vera, Prostate Cancer,Renal Cell Carcinoma, Retinoblastoma, Salivary Gland Cancer, Sarcoma,Skin Cancer, Small Intestine Cancer, Stomach Cancer, Testicular Cancer,Thymoma, Thyroid Cancer, Uterine (Endometrial) Cancer, Vaginal Cancer,and/or Wilms' Tumor. Treatment of cancer may include killing ordestroying cancer cells, reducing cancer proliferation, reducing tumorsize, etc.

The therapeutic agents (compositions) described herein may include anexcipient, diluent, or carrier, typically excluding cetyl alcohol. Thus,described herein are anti-pathogenic (e.g., antibacterial and/orantiviral and/or antifungal and/or antimicrobial) compounds and methodsof using them. The compounds and methods of making and using themdescribed herein are based, in part, on the discovery of mixtures of oneor more amino acids and one or more fatty acids (e.g., C4-C18) to form amixture having specific ranges of ratios or percentages of eachcomponent of the mixture. When the components are within the desiredranges in the mixture, the composition exhibits broad anti-pathogenictherapeutic properties spanning both gram-positive (including acid fastgram-positive bacteria, such as mycobacteria) and gram-negativebacteria, as well as certain pathogenic fungi and viruses. Surprisingly,outside of these defined ranges the anti-pathogenic activity issignificantly lost, particularly with respect to certain categories ofpathogens, including in particular gram-negative bacteria.

These compositions may be used to directly treat a patient (e.g., humanor non-human animals) exposed or potentially exposed to a pathogen, tosanitize surfaces, including medical surfaces, as a coating for amedical device or implant, or in any other use in which ananti-pathogenic material would be useful. The compositions describedherein also appear to have little direct negative effect on patients(e.g., toxicity). Thus, as mentioned, the therapeutic compositionsdescribed herein explicitly include sanitizing compositions that may beused to disinfect and/or sanitize a surface, including skin. Forexample, the therapeutic compositions and methods of using them includehand sanitizer compositions (and methods of using them to sanitize handsor other skin surfaces), as well as disinfectant compositions (andmethods of using them to disinfect, e.g., skin, furniture, equipment,inanimate objects, including but not limited to medical equipment,computer equipment, cooking equipment, tools, cutlery, dishes,doorknobs, floors, walls, benches, etc.).

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art towhich this invention belongs. The following references provide one ofskill with a general definition of many of the terms used in thisinvention: Singleton et al., Dictionary of Microbiology and MolecularBiology (2nd ed. 1994); The Cambridge Dictionary of Science andTechnology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R.Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, TheHarper Collins Dictionary of Biology (1991). As used herein, thefollowing terms have the meanings ascribed to them unless specifiedotherwise. The definitions for amino acids may be as described by theNational Center for Biotechnology Information, NCBI.

As used herein, the terms below have the meanings indicated.

The term “acyl” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocyclyl, or any other moiety where the atom attached to thecarbonyl is carbon. An “acetyl” group refers to a —C(O)CH3 group.

An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attachedto the parent molecular moiety through a carbonyl group. Examples ofsuch groups include methylcarbonyl and ethylcarbonyl. Examples of acylgroups include formyl, alkanoyl and aroyl.

The term “alkenyl” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds optionally substituted and containing from 2 to 20,preferably 2 to 6, carbon atoms. Alkenyl refers to a carbon-carbondouble bond system attached at two or more positions such as ethenylene[(—CH═CH—), (—C::C—)]. Examples of alkenyl radicals include ethenyl,propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.

The term “alkoxy” as used herein, alone or in combination, refers to analkyl ether radical, optionally substituted wherein the term alkyl is asdefined below. Examples of alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical optionally substitutedcontaining from 1 to 20 and including 20, preferably 1 to 10, and morepreferably 1 to 6, carbon atoms. Alkyl groups may be optionallysubstituted as defined herein. Examples of alkyl radicals includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl and the like.

The term “alkylamino” as used herein, alone or in combination, refers toan alkyl group optionally substituted attached to the parent molecularmoiety through an amino group. Alkylamino groups may be mono- ordialkylated, forming groups such as, for example, N-methylamino,N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylthio” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof alkyl thioether radicals include methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20, preferably from 2 to 6, morepreferably from 2 to 4, carbon atoms. “Alkynyl” refers to acarbon-carbon triple bond attached at two positions such as ethynylene(—C:::C—, —C≡C—). Examples of alkynyl radicals include ethynyl,propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl,3-methylbutyn-1-yl, hexyn-2-yl, and the like.

The term “amido” as used herein, alone or in combination, refer to anamino group as described below attached to the parent molecular moietythrough a carbonyl group, or vice versa.

The term “amino” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, any of which may themselves beoptionally substituted.

The term “aryl” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch rings may be attached together in a pendent manner or may be fusedoptionally substituted with at least one halogen, an alkyl containingfrom 1 to 3 carbon atoms, an alkoxyl, an aryl radical, a nitro function,a polyether radical, a heteroaryl radical, a benzoyl radical, an alkylester group, a carboxylic acid, a hydroxyl optionally protected with anacetyl or benzoyl group, or an amino function optionally protected withan acetyl or benzoyl group or optionally substituted with at least onealkyl containing from 1 to 12 carbon atoms.

The terms “arylalkyl” or “aralkyl” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “aryloxy” as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxygenatom.

The term “polyether radical” means a polyether radical containing from 2to 6 carbon atoms interrupted with at least one oxygen atom, such asmethoxymethyl, ethoxymethyl or methoxyethoxymethyl radicals ormethoxyethyl.

The terms “benzo” and “benz” as used herein, alone or in combination,refer to the divalent radical C6H4=derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The terms “carbamate” and “carbamoyl” as used herein, alone or incombination, refers to an ester of carbamic acid (—NHCOO—) which may beattached to the parent molecular moiety from either the nitrogen or acidend, and which may be optionally substituted as defined herein.

The term “carbonyl” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxy” as used herein, refers to —C(O)OH or thecorresponding “carboxylate” anion, such as is in a carboxylic acid salt.An “0 carboxy” group refers to a RC(O)O— group, where R is as definedherein. A “C carboxy” group refers to a —C(O)OR groups where R is asdefined herein.

The term “chemical stability” according to the invention means that thecontent exhibits very little variation with respect to the initialcontent, namely, that the variation in content of active principle atthe time T should not be less than 90% to more particularly than 95% ofthe initial content at TO.

The term “cyano” as used herein, alone or in combination, refers to —CN.

The term “cycloalkyl” or, alternatively, “carbocycle”, as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety contains from 3 to 12, preferably five to seven, carbon atom ringmembers and which may optionally be a benzo-fused ring system which isoptionally substituted as defined herein. Examples of such cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl andthe like. “Bicyclic” and “tricyclic” as used herein are intended toinclude both fused ring systems, such as decahydonapthalene,octahydronapthalene as well as the multicyclic (multicentered) saturatedor partially unsaturated type. The latter type of isomer is exemplifiedin general by, bicyclo[1,1,1]pentane, camphor, adamantane, andbicyclo[3,2,1]octane.

The term “ester” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether” as used herein, alone or in combination, refers to anoxygen atom bridging two moieties linked at carbon atoms.

The terms “halo” or “halogen” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkyl” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CHF—),difluoromethylene (—CF2-), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. Up to two heteroatoms may be consecutive, such as,for example, —CH2-NH—OCH3.

The term “heteroaryl” as used herein, alone or in combination, refers to3 to 7 membered, preferably 5 to 7 membered, unsaturatedheteromonocyclic rings, or fused polycyclic rings in which at least oneof the fused rings is unsaturated, wherein at least one atom is selectedfrom the group consisting of O, S, and N. The term also embraces fusedpolycyclic groups wherein heterocyclic radicals are fused with arylradicals, wherein heteroaryl radicals are fused with other heteroarylradicals, or wherein heteroaryl radicals are fused with cycloalkylradicals. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl,imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl,indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl,benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl,benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl,tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclicheterocyclic groupsincludecarbazolyl, benzidolyl, phenanthrolinyl,dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocyclyl”, asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic radical containing at least one, preferably 1 to4, and more preferably 1 to 2 heteroatoms as ring members, wherein eachsaid heteroatom may be independently selected from the group consistingof nitrogen, oxygen, and sulfur, and wherein there are preferably 3 to 8ring members in each ring, more preferably 3 to 7 ring members in eachring, and most preferably 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocyclyl” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Heterocyclyl groupsof the invention are exemplified by aziridinyl, azetidinyl,1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Theheterocyclyl groups may be optionally substituted unless specificallyprohibited.

The term “hydroxyl” as used herein, alone or in combination, refers to—OH.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of this invention.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower” as used herein, alone or in combination, meanscontaining from 1 to and including 6 carbon atoms.

The term “negatively-charged ion” as used herein, refers to anynegatively-charged ion or molecule, either inorganic (e.g., Cl—, Br—,I—) or organic (e.g., TsO—(i.e., tosylate)).

The term “nitro” as used herein, alone or in combination, refers to—NO2.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamino group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, arylthio,lower alkylsulfinyl, lower alkylsulfonyl, arylsulfinyl, arylsulfonyl,arylthio, sulfonate, sulfonic acid, trisubstitutedsilyl, N3, SH, SCH3,C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate,and lower urea. Two substituents may be joined together to form a fusedfive-, six-, or seven-membered carbocyclic or heterocyclic ringconsisting of zero to three heteroatoms, for example formingmethylenedioxy or ethylenedioxy. An optionally substituted group may beunsubstituted (e.g., —CH2CH3), fully substituted (e.g., —CF2CF3),monosubstituted (e.g., —CH2CH2F) or substituted at a level anywherein-between fully substituted and monosubstituted (e.g., —CH2CF3). Wheresubstituents are recited without qualification as to substitution, bothsubstituted and unsubstituted forms are encompassed. Where a substituentis qualified as “substituted,” the substituted form is specificallyintended. Additionally, different sets of optional substituents to aparticular moiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

Asymmetric centers exist in the compounds of the present invention.These centers are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and 1-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds of the present invention may exist as geometric isomers. Thepresent invention includes all cis, trans, syn, anti, entgegen (E), andzusammen (Z) isomers as well as the appropriate mixtures thereof.Additionally, compounds may exist as tautomers; all tautomeric isomersare provided by this invention. Additionally, the compounds of thepresent invention can exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. In general, the solvated forms are considered equivalent to theunsolvated forms for the purposes of the present invention.

Optical isomers are compounds with the same molecular formula but differin the direction they rotate plane polarized light. There are two typesof optical isomers. The first type of optical isomers are compounds thatare mirror images of one another but cannot be superimposed on eachother. These isomers are called “enantiomers.” The second type ofoptical isomers are molecules that are not mirror images but eachmolecule rotates plane polarized light and are consideredoptically-active. Such molecules are called “diastereoisomers.”Diasteroisomers differ not only in the way they rotate plane polarizedlight, but also their physical properties. The term “optical isomer”comprises more particularly the enantiomers and the diastereoisomers, inpure form or in the form of a mixture.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

The term “imaging agent” as used herein refers to any moiety useful forthe detection, tracing, or visualization of a compound of the inventionwhen coupled thereto. Imaging agents include, e.g., an enzyme, afluorescent label (e.g., fluorescein), a luminescent label, abioluminescent label, a magnetic label, a metallic particle (e.g., agold particle), a nanoparticle, an antibody or fragment thereof (e.g., aFab, Fab′, or F(ab′)2 molecule), and biotin. An imaging agent can becoupled to a compound of the invention by, for example, a covalent bond,ionic bond, van der Waals interaction or a hydrophobic bond. An imagingagent of the invention can be a radiolabel coupled to a compound of theinvention, or a radioisotope incorporated into the chemical structure ofa compound of the invention. Methods of detecting such imaging agentsinclude, but are not limited to, positron emission tomography (PET),X-ray computed tomography (CT) and magnetic resonance imaging (MRI).

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder.This amount will achieve the goal of reducing or eliminating the diseaseor disorder.

The term “therapeutically acceptable” refers to those compounds (orsalts, esters, prodrugs, tautomers, zwitterionic forms, etc. thereof)which are suitable for use in contact with the tissues of patientswithout undue toxicity, irritation, and allergic response, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

As used herein, reference to “treatment” of a patient may include orexclude prophylaxis. The term “treatment” or “treating” is an approachfor obtaining beneficial or desired results including clinical results.For example, beneficial or desired results include, but are not limitedto, one or more of the following: decreasing symptoms resulting from thedisease, increasing the quality of life of those suffering from thedisease, decreasing the dose of other medications required to treat thedisease, delaying the progression of the disease, and/or prolongingsurvival of individuals.

In reference to cancers or other unwanted cell proliferation, beneficialor desired results include shrinking a tumor (reducing tumor size);decreasing the growth rate of the tumor (such as to suppress tumorgrowth); reducing the number of cancer cells; inhibiting, retarding orslowing to some extent and preferably stopping cancer cell infiltrationinto peripheral organs; inhibiting (slowing to some extent andpreferably stopping) tumor metastasis; inhibiting tumor growth;preventing or delaying occurrence and/or recurrence of tumor, and/orrelieving to some extent one or more of the symptoms associated with thecancer. In some embodiments, beneficial or desired results includepreventing or delaying occurrence and/or recurrence, such as of unwantedcell proliferation.

Described herein are compositions (including pharmaceuticalcompositions) for use in treating, preventing, and/or delaying the onsetand/or development of cancer and other methods described herein. Incertain embodiments, the composition comprises a pharmaceuticalformulation which is present in a unit dosage form.

Also provided are articles of manufacture comprising a compound of thedisclosure or a salt thereof, composition, and unit dosages describedherein in suitable packaging for use in the methods described herein.Suitable packaging is known in the art and includes, for example, vials,vessels, ampules, bottles, jars, flexible packaging and the like. Anarticle of manufacture may further be sterilized and/or sealed.

The term “patient” means mammals and non-mammals. Mammals means anymember of the mammalian class including, but not limited to, humans;non-human primates such as chimpanzees and other apes and monkeyspecies; farm animals such as cattle, horses, sheep, goats, and swine;domestic animals such as rabbits, dogs, and cats; laboratory animalsincluding rodents, such as rats, mice, and guinea pigs; and the like.Examples of non-mammals include, but are not limited to, birds, and thelike. The term “patient” does not denote a particular age or sex.

As mentioned above, a treatment (e.g., a method of treating a patient),using any of the compositions described herein including a complex offatty acid:amino acid (e.g., a C8-C20 fatty acid:Arginine, Lysine orHistidine) may include a method of sanitizing a patient's skin and/orsanitizing a surface that will come into contact with a patient.Sanitizing may include sanitizing against bacterial and/or viral and/orfungal pathogens.

For example, sanitizing (and a method of sanitizing using any of thecompositions described herein) may include sanitizing a surface byeliminating x % of the pathogens on an untreated surface, such aseliminating 30%, 50%, 75%, 80%, 90%, 95%, 99%, 99.5%, 99.9%, orsubstantially all of the pathogens on the surface.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds of the present invention may also exist asprodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism:Chemistry, Biochemistry, and Enzymology, Testa, Bernard and Wiley-VHCA,Zurich, Switzerland 2003. Prodrugs of the compounds described herein arestructurally modified forms of the compound that readily undergochemical changes under physiological conditions to provide the compound.Additionally, prodrugs can be converted to the compound by chemical orbiochemical methods in an ex vivo environment. For example, prodrugs canbe slowly converted to a compound when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the compound, or parent drug. They may, for instance, bebio-available by oral administration whereas the parent drug is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. A wide variety of prodrug derivatives are known inthe art, such as those that rely on hydrolytic cleavage or oxidativeactivation of the prodrug. An example, without limitation, of a prodrugis a compound that is administered as an ester (the “prodrug”), but thenis metabolically hydrolyzed to the carboxylic acid, the active entity.Additional examples include peptidyl derivatives of a compound.

In general, the therapeutic compositions described herein include thesalt forms of these compositions. The compounds of the invention canexist as therapeutically acceptable salts. The present inventionincludes compounds listed above in the form of salts, including but notlimited to acid addition salts. Suitable salts include those formed withboth organic and inorganic acids. Such acid addition salts will normallybe pharmaceutically acceptable. However, salts of non-pharmaceuticallyacceptable salts may be of utility in the preparation and purificationof the compound in question. Basic addition salts may also be formed andbe pharmaceutically acceptable. For a more complete discussion of thepreparation and selection of salts, refer to Stahl, P. Heinrich,Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCHA,Zurich, Switzerland (2002). Thus, described herein are salts of thecomplex of fatty acid:amino acid (e.g., a C8-C20 fatty acid:Arginine,Lysine or Histidine).

The term “therapeutically acceptable salt” as used herein, representssalts or zwitterionic forms of the compounds of the present inventionwhich are water or oil-soluble or dispersible and therapeuticallyacceptable as defined herein. The salts can be prepared during the finalisolation and purification of the compounds or separately by reactingthe appropriate compound in the form of the free base with a suitableacid. Representative acid addition salts include acetate, adipate,alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds of the present invention can be quaternized withmethyl, ethyl, propyl, and butyl chlorides, bromides, and iodides;dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl,myristyl, and steryl chlorides, bromides, and iodides; and benzyl andphenethyl bromides. Examples of acids which can be employed to formtherapeutically acceptable addition salts include inorganic acids suchas hydrochloric, hydrobromic, sulfuric, and phosphoric, and organicacids such as oxalic, maleic, succinic, and citric. Salts can also beformed by coordination of the compounds with an alkali metal or alkalineearth ion. Hence, the present invention contemplates sodium, potassium,magnesium, and calcium salts of the compounds of the compounds of thepresent invention and the like.

Compositions

The compositions and therapies described herein may be used toeffectively kill and/or inhibit pathogens and/or cancers. Specifically,the compositions may kill or inhibit bacterial growth and may, at thesame time, aid in healing, including (but not limited to) wound healing.The compositions described herein (anti-pathogenic compositions) maycontain therapeutically-effective amounts of one or more amino acids andone or more fatty acids (e.g., UCA and Arginine, Decanoic acid andArginine, etc.). The combination of these compounds within the specifiedratio ranges may exert a synergistic, not additive, biological mechanismof action that may prevent infection and aid in healing by, e.g.,inhibiting pathogen growth and/or enhancing pathogen death(elimination). Furthermore, the compositions described herein may confergreater therapeutic benefit to a treated patient (e.g., a human) thanthe sequential administration of the substituent compounds. Further,these compositions have been demonstrated to have anti-cancertherapeutic effects, including, but not limited to, inhibiting thegrowth and/or spread of cancer cells (including tumors).

Thus, the compositions and therapies described herein may be useful fortreating symptoms, conditions, and diseases caused by pathogenicinfections in a patient (e.g., a human) and/or cancers. Also describedherein are pharmaceutical preparations and the medicaments obtainedtherefrom. The methods and formulations to prepare the compositionsdescribed herein are disclosed here.

The combinations of a standard (i.e., canonical) or non-standard (i.e.,non-canonical) amino acid (in the D or L isomer), and particularly anamino acid having an electrically charged basic side chain, with anunsaturated or saturated fatty acid (e.g., a C4-C18 fatty acid, aC8-C18, a C4-C20, a C4-C18, etc.) may be used to form a mixture thatproduces a rapid, potent bactericidal effect in both gram-positive andgram-negative bacteria. The proportion of these mixture components(e.g., amino acid and fatty acid) within the mixture may be optimizedfor the anti-pathogenic effect.

For example, in compositions in which the complex of fatty acid:aminoacid includes Arginine, the arginine may be either L-Arginine,D-arginine or both. In some variations, the Arginine may be primary orexclusively L-Arginine (LARG).

As used herein, an anti-pathogenic material includes antibacterial(bactericidal) compositions. A bactericide may be considered as achemical entity producing a bacterial kill rate that is greater than therate of bacterial growth over time, whereas a bacteriostat may beconsidered as a chemical entity that inhibits bacterial reproduction butdoes not directly kill the bacteria.

Examples of unsaturated fatty acids (in addition to those describedabove), may include, but are not limited to, crotonic acid (CAS RegistryNumber 107-93-7), myristoleic acid (CAS Registry Number 544-64-9),palmitoleic acid (CAS Registry Number 373-49-9), sapienic acid (CASRegistry Number 17004-51-2), elaidic acid (CAS Registry Number112-79-8), vaccenic acid (CAS Registry Number 506-17-2), gadoleic acid(CAS Registry Number 29204-02-2), eicosenoic acid (CAS Registry Number5561-99-9), erucic acid (CAS Registry Number 112-86-7), nervonic acid(CAS Registry Number 506-37-6), linoleic acid (CAS Registry Number60-33-3, 463-40-1), pinolenic acid (CAS Registry Number 16833-54-8),eleostearic acid (PubChem #5281115), mead acid (CAS Registry Number20590-32-3), dihomo-gama-linolenic acid (CAS Registry Number 1783-84-2),eicosatrienoic acid (CAS Registry Number 17046-59-2), stearidonic acid(CAS Registry Number 20290-75-9), arachidonic acid (CAS Registry Number506-32-1), eicosatetraenoic acid (PubChem #231), adrenic acid (CASRegistry Number 28874-58-0), bosseopentaenoic acid (CAS Registry Number133205-91-1), eicosapentaenoic acid (CAS Registry Number 10417-94-4),ozubondo acid (CAS Registry Number 25182-74-5), tetracosanolpentaenoicacid, docosahexaenoic acid (CAS Registry Number 6217-54-5), and oleicacid (CAS Registry Number 112-80-1).

Examples of saturated fatty acids include (in addition to thosedescribed above), but are not limited to, propanoic acid (CAS RegistryNumber 79-09-04), butanoic acid (CAS Registry Number 107-92-6),pentanoic acid (CAS Registry Number 109-52-4), hexanoic acid (CASRegistry Number 142-62-1), heptanoic acid (CAS Registry Number111-14-8), octanoic acid (CAS Registry Number 124-07-2), nonanoic acid(CAS Registry Number 112-05-0), decanoic acid (CAS Registry Number334-48-5), undecanoic acid (CAS Registry Number 112-37-8), dodecanoicacid (CAS Registry Number 143-07-7), tridecanoic acid (CAS RegistryNumber 638-53-9), tetradecanoic acid (CAS Registry Number 544-63-8),pentadecanoic acid (CAS Registry Number 1002-84-2), hexadecanoic acid(CAS Registry Number 57-10-3), heptadecanoic acid (CAS Registry Number506-12-7), octadecanoic acid (CAS Registry Number 57-11-4), nonadecanoicacid (CAS Registry Number 646-30-0), eicosanoic acid (CAS RegistryNumber 506-30-9), heneicosanoic acid (CAS Registry Number 2363-71-5),docosanoic acid (CAS Registry Number 112-85-6), tricosanoic acid(PubChem #17085), tetracosanoic acid (CAS Registry Number 557-59-5),pentacosanoic acid (PubChem #10468), hexacosanoic acid (CAS RegistryNumber 506-46-7), heptacosanoic acid (PubChem #23524), octacosanoic acid(CAS Registry Number 506-48-9), nonacosanoic acid (PubChem #20245),triacontanoic acid (CAS Registry Number 506-50-3), henatriacontanoicacid (CAS Registry Number 28232-01-8), dotriacontanoic acid (CASRegistry Number 3625-52-3), tritriacontanoic acid (CAS Registry Number38232-03-0), tetratriacontanoic acid (CAS Registry Number 506-50-3),pentatriacontanoic acid (PubChem #5282595), hexatriacontanoic acid (CASRegistry Number 4299-38-1), and heptatriacontanoic acid (PubChem#5282597).

As mentioned above, in some variations the particular fatty acids ofinterest herein are C11 fatty acids, such as undecylenic acid. The C11fatty acids include molecules that include the eleven carbons similar toundecylenic acid and may be combined with other moieties. Other fattyacids of interest may include C4-C20 fatty acids, including inparticular unbranched C4-C20 fatty acids, such as (but not limited to):decanoic acid and octanoic acid (e.g., C4-C18, C8-C18, C8-C20, etc.).

A standard (canonical) or non-standard (non-canonical) amino acid isdefined as: an organic compound containing an amine (—NH2) and acarboxyl (—COOH) functional group along with a side chain (R group)specific to each amino acid. This includes proteinogenic andnon-proteinogenic amino acids. This includes both D and L isomers(enantiomers). To include the following amino acids in both the D and Lisomers, but not limited to: alanine, arginine, asparagine, asparticacid, cysteine, glutamic acid, glutamine, glycine, Histidine,isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,threonine, tryptophan, tyrosine, valine, selenocysteine, andpyrrolysine. Amino acids having electrically charged basic side chainsare of particular interest herein. Aliphatic amino acids include:alanine, arginine, asparagine, aspartic acid, cysteine, glutamine,glutamic acid, glycine, isoleucine, lysine, leucine, methionine, serine,threonine, and valine. Non-aliphatic amino acids may include: aromaticamino acids (e.g. phenylalanine, Histidine, tyrosine, tryptophan) andimino amino acids (e.g. proline).

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reaction of a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

A salt of a compound can be made by reacting the appropriate compound inthe form of the free base with the appropriate acid. The novel compoundsdescribed herein can be prepared in a form of pharmaceuticallyacceptable salts that will be prepared from nontoxic inorganic ororganic bases including but not limited to aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally-occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,ethylamine, 2-diethylaminoethano, 1,2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucos amine, Histidine, hydroxylamine, isopropylamine,lysine, methylglucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethylamine, trimethylamine,trishydroxylmethyl amino methane, tripropyl amine, and tromethamine.

If the compounds of the invention are basic, salts could be prepared ina form of pharmaceutically acceptable salts that will be prepared fromnontoxic inorganic or organic acids including but not limited tohydrochloric, hydrobromic, phosphoric, sulfuric, tartaric, citric,acetic, fumaric, alkylsulphonic, naphthalenesulphonic,para-toluenesulphonic, camphoric acids, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, gluconic, glutamic, isethonic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phosphoric, and succinic.

While it may be possible for the compounds of the invention to beadministered as the raw chemical, it is also possible to present them asa pharmaceutical formulation. Accordingly, the present inventionprovides a pharmaceutical formulation comprising a compound or apharmaceutically acceptable salt, ester, prodrug or solvate thereof,together with one or more pharmaceutically acceptable carriers thereofand optionally one or more other therapeutic ingredients. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof. Proper formulation is dependent upon the route ofadministration chosen. Any of the well-known techniques, carriers, andexcipients may be used as suitable and as understood in the art; e.g.,in Remington's Pharmaceutical Sciences. The pharmaceutical compositionsof the present invention may be manufactured in a manner that is itselfknown, e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

Formulations that may be suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. All methodsinclude the step of bringing into association a compound of the presentinvention or a pharmaceutically acceptable salt, ester, prodrug orsolvate thereof (“active ingredient”) with the carrier which constitutesone or more accessory ingredients. In general, the formulations areprepared by uniformly and intimately bringing into association theactive ingredient with liquid carriers or finely divided solid carriersor both and then, if necessary, shaping the product into the desiredformulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds described herein (e.g., anti-pathogenic, and/oranti-cancer compounds) may be formulated for parenteral administrationby injection, e.g., by bolus injection or continuous infusion.Formulations for injection may be presented in unit dosage form, e.g.,in ampoules or in multi-dose containers, with an added preservative. Thecompositions may take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilizing and/or dispersing agents. The formulations maybe presented in unit-dose or multi-dose containers, for example sealedampoules and vials, and may be stored in powder form or in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example, saline or sterile pyrogen-freewater, immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the compounds described herein (e.g., anti-pathogeniccompounds), the compounds of the invention may also be formulated as adepot preparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compounds described herein(e.g., anti-pathogenic compounds) may take the form of tablets,lozenges, pastilles, or gels formulated in conventional manner. Suchcompositions may comprise the active ingredient in a flavored basis suchas sucrose and acacia or tragacanth.

The compounds described herein (e.g., anti-pathogenic compounds) mayalso be formulated in rectal compositions such as suppositories orretention enemas, e.g., containing conventional suppository bases suchas cocoa butter, polyethylene glycol, or other glycerides.

The compounds described herein (e.g., anti-pathogenic compounds) may beadministered topically, that is by non-systemic administration. Thisincludes the application of a compound externally to the epidermis orthe buccal cavity and the instillation of such a compound into the ear,eye and nose, such that the compound does not significantly enter thebloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include solid, liquidor semi-liquid preparations suitable for penetration through the skin tothe site of infection such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. In some examples the active ingredient may comprise, fortopical administration, from 0.001% to 40% w/w, for instance from 1% to5% by weight of the formulation (e.g., 0.001% to 35%, 0.002% to 30%,0.01% to 25%, 0.05% to 20%, 0.1% to 15%, 0.1% to 12.5%, 0.5% to 10%,0.5% to 8%, 1% to 7%, 1% to 6%, 1% to 5%, etc.). It may however comprisemore than 10% w/w (e.g., 20% or less, 25% or less, 30% or less, 35% orless, 40% or less, 45% or less, 50% or less, etc. and/or in somevariations greater than 0.001%, greater than 0.01%, greater than 0.1%,greater than 1%, etc.).

Via the topical route, the pharmaceutical compounds described herein(e.g., anti-pathogenic compounds) may be in the form of liquid or semiliquid such as ointments, or in the form of solid such as powders. Itmay also be in the form of suspensions such as polymeric microspheres,or polymer patches and hydrogels allowing a controlled release. Thistopical composition may be in anhydrous form, in aqueous form or in theform of an emulsion. The compounds may be used topically at aconcentration of between 0.001% and 10% by weight (e.g., between 0.01%and 1% by weight), relative to the total weight of the composition. Insome variations, the compounds may be used topically at greater than 10%by weight (e.g., 20% or less, 25% or less, 30% or less, 35% or less, 40%or less, 45% or less, 50% or less, etc.).

For administration by inhalation, the compounds described herein (e.g.,anti-pathogenic compounds) may be conveniently delivered from aninsufflator, nebulizer pressurized packs or other convenient means ofdelivering an aerosol spray. Pressurized packs may comprise a suitablepropellant such as dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, the compounds according tothe invention may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator. Other potential applications may include industrialapplications, e.g. “micro-biocides”, for use in agriculture, foodproduction, etc.

Preferred unit dosage formulations include those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example, those suitable for oral administration mayinclude flavoring agents.

The compounds described herein (e.g., anti-pathogenic compounds) may beadministered orally or via injection at a dose. Tablets or other formsof presentation provided in discrete units may conveniently contain anamount of compound of the invention which is effective at such dosage oras a multiple of the same. For example, compounds described herein(e.g., anti-pathogenic compounds) can be administered at a daily dose ofabout 0.001 mg/kg to 100 mg/kg of body weight, in 1 to 3 dosage intakes.In some variations, compounds can be used systemically, at aconcentration generally of between 0.001% and 10% by weight andpreferably between 0.01% and 1% by weight, relative to the weight of thecomposition.

The mixture of amino acids and fatty acids (e.g., L-Arg and UCA, L-Argand Decanoic acid, etc.) may be collectively or separately consideredthe active ingredient (or if separately, active ingredients) that may becombined with the carrier materials to produce a single dosage form willvary depending upon the host treated and the particular mode ofadministration.

The compounds described herein (e.g., anti-pathogenic compounds) can beadministered in various modes, e.g. orally, topically, or by injection.The precise amount of compound administered to a patient may be theresponsibility of the attendant physician. The specific dose level forany particular patient may depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diets, time of administration, route ofadministration, rate of excretion, drug combination, the precisedisorder being treated, and the severity of the indication or conditionbeing treated. Also, the route of administration may vary depending onthe condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (e.g., anti-pathogenic compounds), ora pharmaceutically acceptable salt, ester, or prodrug thereof, incombination with another therapeutic agent. By way of example only, ifone of the side effects experienced by a patient upon receiving one ofthe compounds herein is hypertension, then it may be appropriate toadminister an anti-hypertensive agent in combination with the initialtherapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may onlyhave minimal therapeutic benefit, but in combination with anothertherapeutic agent, the overall therapeutic benefit to the patient isenhanced). Or, by way of example only, the benefit of experienced by apatient may be increased by administering one of the compounds describedherein with another therapeutic agent (which also includes a therapeuticregimen) that also has therapeutic benefit. By way of example only, in atreatment for pain involving administration of one of the compoundsdescribed herein, increased therapeutic benefit may result by alsoproviding the patient with another therapeutic agent for pain. In anycase, regardless of the disease, disorder or condition being treated,the overall benefit experienced by the patient may simply be additive ofthe two therapeutic agents or the patient may experience a synergisticbenefit.

Specific, non-limiting examples of possible combinations with thecompounds described herein may include use of the compounds togetherwith inert or active compounds, or other drugs including wetting agents,flavor enhancers, preserving agents, stabilizers, humidity regulators,pH regulators, osmotic pressure modifiers, emulsifiers, UV-A and UV-Bscreening agents, antioxidants, depigmenting agents such as hydroquinoneor kojic acid, emollients, moisturizers, for instance glycerol, PEG 400,or urea, antiseborrhoeic or antiacne agents, such asS-carboxymethylcysteine, S-benzylcysteamine, salts thereof orderivatives thereof, or benzoyl peroxide, antibiotics, for instanceerythromycin and tetracyclines, chemotherapeutic agent, for example,paclitaxel, antifungal agents such as ketoconazole, agents for promotingregrowth of the hair, for example, minoxidil(2,4-diamino-6-piperidinopyrimidine 3-oxide), non-steroidalanti-inflammatory agents, carotenoids, and especially p-carotene,antipsoriatic agents such as anthralin and its derivatives,eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoic acid, andesters and amides thereof, retinoids, e.g., RAR or RXR receptor ligands,which may be natural or synthetic, corticosteroids or oestrogens,alpha-hydroxy acids and a-keto acids or derivatives thereof, such aslactic acid, malic acid, citric acid, and also the salts, amides oresters thereof, or p-hydroxy acids or derivatives thereof, such assalicylic acid and the salts, amides or esters thereof, ion-channelblockers such as potassium-channel blockers, or alternatively, moreparticularly for the pharmaceutical compositions, in combination withmedicaments known to interfere with the immune system, anticonvulsantagents include, and are not limited to, topiramate, analogs oftopiramate, carbamazepine, valproic acid, lamotrigine, gabapentin,phenytoin and the like and mixtures or pharmaceutically acceptable saltsthereof. A person skilled in the art will take care to select the othercompound(s) to be added to these compositions such that the advantageousproperties intrinsically associated with the compounds of the inventionare not, or are not substantially, adversely affected by the envisagedaddition.

In any case, the multiple therapeutic agents (at least one of which is acompound of the present invention) may be administered in any order oreven simultaneously. If simultaneously, the multiple therapeutic agentsmay be provided in a single, unified form, or in multiple forms (by wayof example only, either as a single pill or as two separate pills). Oneof the therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

Thus, in another aspect, methods for treating diseases, disorders,conditions, or symptoms in a patient (e.g., a human or animal) in needof such treatment are presented herein, the methods comprising the stepof administering to the patient an amount of a compound of the inventioneffective to reduce or prevent the disease, disorder, condition, orsymptom, in combination with at least one additional agent for thetreatment of said disorder that is known in the art.

Any of the anti-pathogenic or anti-cancer compositions described hereinmay be formulated for coating a surface, including coating surfaces ofmedical devices to prevent bacteria colonization, biofilm formation andthe development of hospital acquired infections. The application ofmedical devices, including their long-term use, can lead to bacterialcolonization, biofilm formation, and the development ofhospital-acquired bacterial infections, often referred to as nosocomialinfections. This includes catheter-related blood stream infection,orthopedic implantations, ventilator associated pneumonia, surgical siteinfection and catheter associated urinary tract infection. This canresult in the need to remove and/or replace the medical device. Ananti-pathogenic formulation (e.g., including the amino acid and fattyacid) may be applied to the surface of a medical device in a number ofways, including ionic binding to a surface, passive adsorption, orembedding the formulation within a polymer matrix. The formulation maybe used in combination with other molecules, biofilm matrix degradingsubstances or other antibacterial agents. Any medical device may becoated as described herein, including, e.g., implantable medical devices(stents, shunts, vasooclusive coils, grafts, pins, plates, etc.) andnon-implantable devices (catheters, masks, surgical tools, etc.).

Any of the methods (including user interfaces) described herein may beimplemented as software, hardware or firmware, and may be described as anon-transitory computer-readable storage medium storing a set ofinstructions capable of being executed by a processor (e.g., computer,tablet, smartphone, etc.), that when executed by the processor causesthe processor to control perform any of the steps, including but notlimited to: displaying, communicating with the user, analyzing,modifying parameters (including timing, frequency, intensity, etc.),determining, alerting, or the like.

FIG. 26 is a table showing a matrix of examples of fatty acids (C4-C20amino acids) combined with amino acids at a 1:1 molar ratio. Individualcells indicate the ability of each particular combination to form atestable solution and provide an anti-pathogenic/anti-cancer effect. Ascan be seen, amino acids having an electrically charged basic side chain(“electrically charged side chains—basic”), such as Arginine, Histidineand Lysine, demonstrated a robust ability to form a solution and providetherapeutic effects. In this preliminary analysis, Arginine and Lysinewere slightly more robust in forming miscible solutions as compared tohistidine; in addition, although virtually all fatty acids demonstratedthe ability to combine with any of the amino acids having anelectrically charged basic side chain (Arginine, Histidine, Lysine), theC8-C20 fatty acids were slightly more robust. Combinations marked as“no,” or putatively indicated by (−), were found to be immiscible whencombining just the amino acid and the fatty acid at 1:1 molar ratio (andtherefore failed to demonstrate anti-pathogen/anti-cancer effects).

Examples

One example of a therapeutically effective composition is referred toherein as GS-1. GS-1 is a composition of UCA and LARG in which the molarratio of UCA:LARG is between 1:0.6 to 1:1.6. In some variations GS-1include a complex of UCA:LARG in a molar ration of 5:4 (1:0.76 byweight). GS-1 may be made, for example, by heating and stirring 15 g ofLARG into 75 g of water at 65 degrees C. until fully dissolved, and thenadding 19.8 g of UCA while heating and stirring. In some variations,GS-1 is formulated in a molar ratio of 1:1.

FIG. 13 shows the therapeutic efficacy of GS-1 against eight isolates ofmethicillin-resistant Staphylococcus aureus (MRSA) at a drug dilution of1:16. MRSA is gram-positive. In FIG. 13, GS-1 resulted in almostuniversal, complete (100%) killing of the MRSA isolates. In thisexample, bacteria (MRSA isolates) are put onto fresh plates and allowedto grow for 30 hours. A suspension inoculum is made from the plates(e.g., a 1 McFarland solution in sterile water), from which theturbidity may be optically read. A standard inoculum may then becultured in media and 100 μL of that solution combined with 100 μL ofdrug product and grown at various dilutions for 16-20 hrs. Duplicatesmay then be examined (e.g., following pelleting at 7,000 RPM for 15 min,resuspended in PBS and serial dilutions plated and grown for 24 hrs.).Duplicate plates at multiple dilutions may then be imaged and coloniescounted. Treated samples were compared with untreated samples (e.g., inwhich water without UCA and LARG included) and inoculum (showing cellviability).

FIG. 14 illustrates the therapeutic effect of the GS-1 compositionagainst Escherichia coli (EC). Two isolates of Escherichia coli (EC)were examined at a drug dilution of 1:16. As shown the GS-1 compositionresulted in complete (100%) killing of the bacteria at this dilution.The data was collected as described above, showing a comparison betweenuntreated bacteria and inoculum.

Similarly, FIG. 15 illustrates the in-vitro efficacy of GS-1 againstthree isolates of CRE-positive Klebsiella pneumoniae (KPCRE) at a drugdilution of 1:16. As with EC and MRSA, GS-1 resulted in complete killing(100%) of the bacteria for each of the isolates.

FIG. 16 shows a similar effectiveness of GS-1 against two isolates ofPseudomonas aeruginosa (PSA) at a drug dilution of 1:8. In this example,all (100%) of the bacteria were killed. Similar results (>99.9% killed)were seen at a 1:16 dilution (not shown).

GS-1 was also found to have anti-cancer activity. For example, culturedrat glioma cancer cells were treated with GS-1 at increasingly diluteconcentrations, resulting in inhibition of all or nearly all of thecancer cells at concentrations as dilute as 1:128, and significantinhibition at lower (e.g., 1:256 and 1:512) dilution, as shown in FIGS.17 and 18A-18E. For example, in FIG. 17, rat glioma cancer cells werecultured to approximately 90% confluence, trypsinized, and seeded athigh titer (e.g., 4500 per well), allowed to settle and adhere overnightbefore treatment with GS-1 at particular dose dilutions. Serial cellulardilutions for each GS-1 dose were examined, and treated cells werecultured 24 hrs., then the media (including the GS-1) was replaced withfresh media and an MTS assay (based on the reduction of the MTStetrazolium compound by viable cells) was performed to allowquantification of healthy cells by colorimetric change. FIG. 17 showsthe percentage of inhibition of cancer cell proliferation as comparedwith untreated cells.

FIGS. 18A-18E show images of cancer cells treated with increasingdilutions of GS-1 (FIGS. 18A-18D) and untreated (FIG. 18E). Each imageis a microscopic view showing in vitro efficacy of GS-1 in killing C6rat glioma cancer cells, as a function of drug dilution. Each of FIGS.18A-18E show a fluorescent image using a vital (e.g., PI) stain that isoverlaid with a non-fluorescent image to visually show unhealthy cells(dead or dying cancer cells) versus healthy cells. As shown in FIGS.18A-18D, unhealthy cells uptake the PI stain and fluoresce, whereashealthy cells do not. In agreement with FIG. 17, the higher dilutions ofGS-1 (1:64 and 1:128) show near-complete efficacy in killing the cancercells, with almost all cells fluorescing, while at the higher dilutions(e.g., 1:256 and 1:512) there is decreasing efficacy, with fewer cellsfluorescing. No cells in the untreated control, FIG. 18E, arefluorescing. Each of these images were taken at the same exposure toallow comparison.

Companion studies, examining the effect of GS-1 on ‘normal’ cells,including healthy animal cells showed no effect, including at high(undiluted) concentrations, as compared to cancer cells.

Animal studies have also been performed to establish the in vivo safetyand efficacy of GS-1. In one example study, 16 rats were dermallyabraded on a 4×4 cm area and then infected with methicillin resistantStaphylococcus aureus (MRSA). After 24 h, half of the rats were treatedwith GS-1, and half were treated with saline (untreated controls), twicedaily for 7 days. At the end of 7 days, skin swabs and tissue punches atthe site of infection were collected and analyzed for evidence ofinfection (efficacy), and blood was drawn and analyzed for evidence oftoxicity (safety). All rats treated with GS-1 showed no signs ofinfection after 7 days, and showed no signs of toxicity or side-effectscompared to the untreated control animals.

As mentioned above, in general the compositions described herein mayinclude one or more fatty acids and one or more amino acids in a fattyacid:amino acid molar ratio of between about 1:0.6 to about 1:1.6. FIGS.1-18 illustrate compositions in which the fatty acid is UCA and theamino acid is LARG, however, the compositions and methods describedherein are not limited to UCA and LARG. For example, FIG. 20 shows acomparison of a UCA/LARG composition (“GS-1”), with mixtures of Decanoicacid/LARG (“GS-2”), Octanoic acid/LARG (“GS-3”), and Linoleic acid/LARG(“GS-4”), each of which showed significant anti-pathogenic activity atcomparable concentrations, and as compared to untreated conditions andan inoculum control. For example, in each of these examples in FIG. 20,the fatty acid to amino acid in the compositions was at a ratio of about1:0.76 (fatty acid:amino acid) by weight when diluted and used to treatMRSA. GS-1, GS-2 and GS-3 all had fatty acid:amino acid aqueous mixtureswith approximately 32% w/w of total active pharmaceutical ingredients(APIs), which were diluted at 1:128 in water, resulting in aconcentration of about 0.25% w/w total APIs. GS-4 had a concentration ofabout 1.64 mg/mL (0.16% w/w) total APIs. In FIG. 20, GS-1 and GS-2resulted in near-total bactericidal effect on the MRSA (shown by thelack of bar), while GS-3 and GS-4 had a substantial reduction in MRSAcompared to untreated control. Note that GS-4 was used at a lowerconcentration than GS-1 to GS-3 (e.g., 0.16% w/w total APIs, rather than0.25% w/w for GS-1 to GS-3). All of these results indicated an efficacythat is comparable or superior to commercially available antibiotics,such as the topical antibiotic mupirocin (“Bactroban”).

FIGS. 21-23 illustrate specific results for each of GS-2, GS-3 and GS-4.FIG. 21 shows the activity of a composition of Decanoic acid and LARG(at a 1:0.76 ratio by weight). In FIG. 21, the treated concentration wasabout 2.51 mg/mL (0.25% w/w) of total API (e.g., of Decanoic acid andLARG). Six individual clinical isolates were treated with GS-2 insolution for 24 hours, and resulted in complete killing of all of theMRSA present (e.g., 100% bactericidal).

FIG. 22 shows a similar assay using a composition including a 1:0.76 w/wratio of Octanoic acid to LARG (GS-3). The concentration of the Octanoicacid/LARG in the treatment solution was 2.52 mg/mL (0.25% w/w) for thetotal API, and was added to six clinical MRSA isolates and treated for24 hours. In this assay the GS-3 (Octanoic acid/LARG) produced aninhibitory effect in 66.7% of the isolates and a bacteriostatic effectin 33.3%. The concentration of the Octanoic acid/LARG composition may beincreased to get a complete bactericidal effect.

FIG. 23 shows an example in which a mixture of Linoleic acid and LARG(GS-4) were combined. In this example, the C18 Linoleic acid was used totreat six MRSA clinical isolates at a concentration of 1.64 mg/mL (0.16%w/w) total API for 24 hours in solution. The GS-4 mixture resulted in abactericidal effect in 50% of the isolates and an inhibitory effect in50%.

FIG. 24 illustrates one example of a composition of fatty acid and aminoacid having a ratio of 1:0.76 w/w, as described above. In this example,the fatty acid is UCA and the amino acid is Lysine (GS-5). As shown inFIG. 24, five clinical isolates of MRSA were treated with GS-5(UCA/Lysine) at a concentration of 2.46 mg/mL (0.25% w/w) total API in asolution for 24 hours. The GS-5 composition resulted in a bactericidaleffect in all isolates, as shown (note the logarithmic scale).

Similarly, FIG. 25 illustrates an example of a composition of fatty acidand amino acid, where the amino acid is Histidine. The complex ofHistidine and UCA may have a ratio of 1:0.76 w/w (e.g., a molar ratio ofabout 1.25:1 UCA:Histidine). As shown in FIG. 25, the Histidine had aclear bactericidal and bacteriostatic effect against Methicillinsensitive Staphylococcus aureus (MSSA). In this example, four clinicalisolates were treated with GS-6 (UCA:Histidine as descried above) at aconcentration of 2.71 mg/ML (0.25% w/w) total API in solution for 24hours. GS-6 produced a bactericidal effect in all of the isolates(100%), as shown in FIG. 25.

Thus, based on the data and other experiments in which the amino acidswere varied with positive charged (basic at physiological pH) fattyacids (e.g., UCA:L-ARG, UCA:Lysine, and UCA:Histinde) whereas otheramino acids were less effective (or ineffective, such as D-Arginine, andother non-charged amino acids) in evoking a bactericidal effect. Thus insome variations, the amino acid may be limited to a charged (andparticularly the positively charged) amino acids, such as amino acidhaving an electrically charged basic side chain.

Combination with Other Active Agent(s)

In general, any of the therapeutic compositions described herein mayinclude one or more additional components that may act as or enhance theactivity of the fatty acid and amino acid. For example, any of thetherapeutic compositions described herein may be combined with one ormore additional active ingredients to provide different or enhancedproperties, such as enhanced efficacy.

In some variations the compositions described herein may include anadditional agent that disrupts cell membranes. In some variations, thecompositions described herein may include an antibiotic, such as apolymyxin (e.g. polymyxin B or polymyxin E) to further enhance efficacy.In general, the therapeutic compositions described herein may becombined with one or more non-ribosomal peptides (e.g., actinomycin,bacitracin, daptomycin, vancomycin, teixobactin, tyrocidine, gramicidin,zwittermicin A, ACV-Tripeptide, epothilone, bleomycin, ciclosporin(Cyclosporine A), etc.). The addition of an additional component, suchas polymyxin, with the compositions described herein may permit asubstantially lower amount of antibiotic to be used and/or maydramatically potentiate the efficacy of the antibiotic.

For example, in some variations, the compositions described herein mayinclude polymyxin B nonapeptide at a concentration (final therapeuticcomposition) of between about 0.1 μg/mL to about 50 μg/mL, such asbetween about 0.1 μg/mL to 30 μg/mL, between about 0.1 μg/mL to about 25μg/mL, between about 0.1 μg/mL to about 20 μg/mL, between about 0.5μg/mL to about 30 μg/mL, etc. Preliminary data has shown thatcompositions of GS-13 (e.g., Lauric acid:Lysine) at a molar ratio asdescribed herein, e.g., between about 1:0.8 and 1:1.2 (e.g., about 1:1)in combination with polymyxin B nonapeptide may have a strikinglysynergistic effect, such that the amount of polymyxin B nonapeptide(e.g., 0.1 μg/mL to about 50 μg/mL) which, on its own, may have littleif any pathogenicity (e.g., bacterial cytotoxicity) when combined withlower final concentrations of GS-13 below the normal GS-13 minimumbactericidal concentration (e.g., below 1 μg/mL) may be stronglyanti-pathogenic, including strongly bactericidal. The combination ofGS-13 (or other fatty acid:amino acid complexes as described herein,including GS-1, GS-2, GS-3, GS-4, GS-5, GS-6, GS-7, GS-8, GS-9, GS-10,GS-11, GS-12, etc.) with other drugs, active ingredients or inactiveingredients may result in a much more potent therapeutic composition.This may allow both active ingredients (e.g., GS-13 and polymyxin Bnonapeptide) to be used at lower levels that would otherwise beineffective, but may also avoid side effects. Without being bound bytheory, in variations in which the complex of fatty acid:amino acidforms a lamellar supramolecular structure, as described herein, thelamellar structures may function as a delivery vehicle, in which thepolymyxin B nonapeptide is packaged within the lamellar supramolecularstructure formed by the fatty acid:amino acid complex (e.g., GS-13 orany of the other fatty acid:amino acid complexes described herein).

Minimum Bactericidal Concentration

FIG. 36 is a table summarizing the results examining the bactericidaleffects of a variety of examples of composition including a complex offatty acid and amino acid, as described herein. In FIG. 36, the tableshows the minimum bactericidal concentration of GS-9 (Arachidonicacid:Lysine) in an approximately 1:1 molar ratio, GS-10 (Lauricacid:Arginine) in an approximately 1:1 molar ratio, GS-11 (Lauricacid:Lysine) in an approximately 1:1 molar ratio, GS-12 (Linoleicacid:Lysine) in an approximately 1:1 molar ratio, and GS-13 (Lauricacid:Lysine) in an approximately 1:1 molar ratio, against a variety ofbacterial cell types, including MRSA, E. coli, K. pneumonia, A.baumannii, and E. cloacae. As mentioned above, when a second activeingredient (e.g., polymyxin B nonapeptide) was included with the complexof fatty acid:amino acid (e.g., GS-9, for example), the minimumbactericidal concentration dropped by more than 10× (and in somevariations 100×) (data not shown).

Although FIG. 35 includes only four examples of solutions of complexesof fatty acids and amino acids, this data is representative and typicalof the results shown across a variety of fatty acids complexed withArginine, Lysine and/or Histidine.

FIG. 37 shows EC₅₀ data for GS-12 (Linoleic acid:Lysine) in anapproximately 1:1 molar ratio tested against a variety of virus types.The results indicate that relatively low concentrations of a solution ofa complex of fatty acid and amino acid may have a robust andbroad-spectrum antiviral effect.

As discussed above, the compositions described herein have bothanti-pathogenic (e.g., anti-bacterial, anti-viral, anti-fungal, etc.)efficacy as well as anti-cancer efficacy. For example, returning now toFIG. 27, this figure shows a graph summarizing test results for oneexample of a composition as described herein, GS-1 (UCA:LARG) in anapproximately 1:1 molar ratio. In this example, in vitro activityagainst human cancer cells is shown. The graph shows untreated andtreated values for each of a variety of cancer cell lines. All resultsare for a working drug concentration of 0.3% w/w. All of the examinedcancer cell lines showed a marked reduction in cancer cell viability 24hours after exposure to the composition, as measured by opticalabsorbance (e.g., absorbance at 493 nm). In this example, each ofprostate cancer cells, breast cancer cells, melanoma cancer cells,Leukemia cells and lung cancer cells showed a reduction followingtreatment with 0.3% of the GS-1 solution.

FIGS. 28-32 illustrate the anti-cancer effects of one example of thetherapeutic composition (e.g., GS-1) described herein. Similar resultsare seen, or predicted to be seen, with the other therapeuticcompositions comprising a mixture of a fatty acid:amino acid in a molarratio of between about 1:0.6 to about 1:1.6, including for virtually anyC4-C20 fatty acid and amino acid (including Arginine, Histidine, and/orLysine, etc.).

For example, FIG. 28 is a graph illustrating the results of acomposition of a mixture of a fatty acid:amino acid in a molar ratio ofbetween about 1:0.6 to about 1:1.6 showing an anti-cancer efficacy onPC3 human prostate cancer cells in culture. The mixture is a mixture ofLARG and UCA, treating human prostate cancer cells. In FIG. 28, therewas a complete reduction in viability of cancer cells following 24 hoursof treatment using 0.30% of the composition (GS-1) and a 99.5% reductionin viability of cultured cancer cells using 0.150% of the composition.PC3 human prostate cancer cells were seeded onto sterile 96 well platesat 7000 cells per well. After 24 hours of growth, the cells were furtherincubated at 37 degrees Celsius with dilutions of GS-1 (GS-1-2) from astock concentration of 30% for 24 hours. After incubation, the media andtest article were removed and replaced with fresh pre-warmed media. 20μL of MTS was added to each well containing 100 μL of media and wasincubated for 2 hours. After incubation, the plate was analyzed on a 96well colorimetric plate reader. Blank subtraction was performed on alldata using 100 μL media and 20 μL MTS absent cells (n=12 wells pertreatment and n=24 wells no treatment). Error bars are standarddeviation.

Similar results were seen with cultured breast cancer cells. Forexample, in FIG. 29, the graph shows MTS cell viability from an assay inwhich MCF7 breast cancer cells were seeded onto sterile 96 well platesat 7000 cells per well. After 24 hours of growth, the cells were furtherincubated at 37 degrees Celsius with dilutions of GS-1 (GS-1-2) from astock concentration of 30% for 24 hours. After incubation, the media andtest article were removed and replaced with fresh pre-warmed media. 20μL of MTS was added to each well containing 100 μL of media and wasincubated for 2 hours. After incubation, the plate was analyzed on a 96well colorimetric plate reader. Blank subtraction was performed on alldata using 100 μL media and 20 μL MTS absent cells (12 wells pertreatment, 12 wells were untreated). Incubation with 0.300% of thecomposition (GS-1) showed an 89.8% decrease in cultured breast cancercell viability.

FIG. 30 shows the results of treatment of cultured human skin cancer(MM170 Human Melanoma cells) following 24 hour treatment. In FIG. 30,MM170 human melanoma cells were seeded onto sterile 96 well plates at7,000 cells per well. As above, after 24 hours of growth, the cells werefurther incubated at 37 degrees Celsius with dilutions of GS-1 (from astock concentration of 30%) for 24 hrs. After incubation, the media andtest article were removed and replaced with fresh pre-warmed media. 20μL of MTS was added to each well containing 100 μL of media and wasincubated for 2 hrs. After incubation the plate analyzed on a 96 wellcolorimetric plate reader. Blank subtraction was performed on all datausing 100 μL media+20 μL MTS absent cells. Treated wells=12 wells. Notreatment wells=24. Error bars represent standard deviation. Complete(e.g., 100%) decrease in viability was seen using a 0.300%concentration.

Treatment of cultured human leukemia cells showed a similar trend;incubation with a solution of 0.075% resulted in a 99.8% decrease inviability of the cultured cells. U937 human leukemia cells were seededonto sterile 96 well plates at 7,000 cells per well. After 24 hours ofgrowth, the cells were further incubated at 37 degrees Celsius withdilutions of GS-1 (from a stock concentration of 30%) for 24 hrs. Afterincubation, the media and test article were removed and replaced withfresh pre-warmed media. 20 μL of MTS was added to each well containing100 μL of media and was incubated for 2 hrs. After incubation the plateanalyzed on a 96 well colorimetric plate reader. Blank subtraction wasperformed on all data using 100 μL media and 20 μL MTS absent cells.Treated wells: n=4 (3 wells per n; 12 total wells). No treatment wellsn=8 (3 wells per n; 24 wells total).

Cultured human lung cancer cells (A549 Human Alveolar AdenocarcinomaCells) also showed a nearly complete reduction (e.g., to 98.8%) inviability following treatment with a 0.30% solution of the GS-1therapeutic composition, As shown in FIG. 32, A549 human lung cancercells were seeded onto sterile 96 well plates at 7,000 cells per well.As described above, after 24 hours of growth, the cells were furtherincubated at 37 degrees Celsius with dilutions of GS-1 (from a stockconcentration of 30%) for 24 hrs. After incubation, the media and testarticle were removed and replaced with fresh pre-warmed media. 20 μL ofMTS was added to each well containing 100 μL and incubated for 2 hrs.After incubation the plate analyzed on a 96 well colorimetric platereader. Blank subtraction was performed on all data using 100 μL mediaand 20 μL MTS absent cells. n=12 wells (3 replicates×4) per treatment.n=35 wells no treatment. Error bars are standard deviation.

Similar anti-cancer results were seen using other combinations of aminoacid and fatty acid, as mentioned above. For example, FIG. 33 is a graphshowing very similar data for GS-2 (a mixture of LARG and Decanoicacid). In FIG. 33, the effect of GS-2 on A549 Human AlveolarAdenocarcinoma cells is shown. At a concentration of 0.300% of GS-2, a98.2% reduction of viability of the lung cancer cells was seen. Asdescribed above for GS-1, A549 human lung cancer cells were seeded ontosterile 96 well plates at 7,000 cells per well. After 24 hours ofgrowth, the cells were further incubated at 37 degrees Celsius withdilutions of GS-2 (from a stock concentration of 30%) for 24 hrs. Afterincubation, the media and test article were removed and replaced withfresh pre-warmed media. 20 μL of MTS was added to each well containing100 μL of media and was incubated for 2 hrs. After incubation the plateanalyzed on a 96 well colorimetric plate reader. Blank subtraction wasperformed on all data using 100 μL media and 20 μL MTS absent cells.n=12 wells (3 replicates×4) per treatment. n=70 wells no treatment.Error bars are standard deviation.

FIG. 38 is a table summarizing the IC50 results of a two additionalexamples of complexes of fatty acid:amino acid, e.g., GS-9 (Arachidonicacid:Lysine) and GS-12 (Linoleic acid:Lysine), each at an approximately1:1 molar ratio when treated against a variety of cancer cell types.These results also show a robust effect at relatively low concentrationon the different cancer types.

As mentioned, these therapeutic compositions of fatty acid:amino acid ina molar ratio of between about 1:0.6 to about 1:1.6 are also potentanti-viral agents. For example, FIG. 34 is a graph showing the efficacyof these therapeutic compositions against HSV infected cells. In thisgraph two concentrations of GS-1 are shown against HSV infected cells(150 μg/mL and 75 μg/mL). FIG. 35 shows a similar result againstpseudo-Ebola infected cells at three working concentrations of oneexample of a therapeutic composition of fatty acid:amino acid (e.g.,GS-1). Preliminary results show the same effect when these therapeuticcompositions are used to treat other viral agents such as influenza andsmallpox.

Thus, the compositions described herein were generally effective againstbacteria, including both gram-positive and gram-negative bacteria. Forexample, GS-1 and GS-2 (as well as all other fatty acid:amino acidtherapeutic compositions within the specified molar ratio tested) showedactive anti-bacterial effects against both gram-positive andgram-negative bacteria. For example, any of the fatty acid:amino acidtherapeutic compositions described herein also showed efficacy againstClostridium difficile (C. difficile) (data not sown).

Systemic Safety

Systemic safety studies from rodents have shown that the therapeuticcompositions described herein (e.g., therapeutic compositions of fattyacid:amino acid in a molar ratio of between about 1:0.6 to about 1:1.6)are safe at even relatively high concentrations. Thus, thesecompositions may be given topically and/or systemically to treat apatient in need thereof (e.g., for anti-pathogenic reasons and/oranti-cancer treatments). For example, in one study, one exemplarycomposition (e.g., GS-1) was administered in a single dose viasubcutaneous injection at a dose level of 1.25 mL/kg at full strength,corresponding to 381 mg/kg of API. No side-effects were observed.

In another study, GS-2 was administered in a single dose viasubcutaneous injection at a dose level of 10 mL/kg at full strength,corresponding to 3,050 mg/kg of API. No side-effects were observed. GS-2was also administered once daily for 14 days via subcutaneous injectionat a dose level of 5 mL/kg at full strength, corresponding to 1,525mg/kg of API. No side-effects were observed.

FIG. 39A illustrates the lack of cytotoxicity of the solutions includinga complex of fatty acid:amino acid as described herein. In FIG. 39A thecomplex of fatty acid:amino acid is GS-1 (undecylenic acid:Arginine) atan approximately 1:1 molar ratio looking for the cytotoxicity of thistherapeutic composition against surrogate normal cells (Vero cells)after an acute treatment, e.g., on day 1. No significant cytotoxicitywas observed for normal cells. Vero cells are a transformed cell line(Green Monkey Kidney) that do not produce tumors and are not consideredcancerous.

In contrast, FIG. 39B is a graph showing cytotoxicity of the samesolution (GS-1) against a cancer cell line, U937 human leukemia cells,over the same time course as FIG. 39A. In this example, however,significant cytotoxicity was observed against the leukemia cells (e.g.,the solution of GS-1 produced a CC₅₀ against the leukemia cells at aconcentration of about 168.9 μg/mL).

Sanitizer/Disinfecting Compositions

As described above, any of the therapeutic compositions described hereinmay be sanitizing and/or disinfecting compositions. For example, any ofthese therapeutic compositions may be used (and may be adapted for use)as a sanitizer and/or disinfecting composition. For example, any ofthese compositions may be used as a hand sanitizer (e.g., forapplication to skin), and/or for use as a disinfecting composition (todisinfect, e.g., skin, furniture, equipment, inanimate objects,including but not limited to medical equipment, computer equipment,cooking equipment, tools, cutlery, dishes, doorknobs, floors, walls,benches, etc.). The compositions described herein may be provided inconcentrated form (e.g., 10× concentration, 20× concentration, 25×concentration, 50× concentration, 100× concentration, etc.) and may bediluted by the user for use, or may be provided already diluted andready for use.

Any of the compositions and methods described herein may include one ormore additional ingredients, including one or more additional inactiveingredients, and/or one or more additional active ingredients. Any ofthe compositions and methods described herein may include one or moresurfactants, and in particular cationic surfactants, such asBenzalkonium chloride (also known as BZK, BKC, BAK, BAC,alkyldimethylbenzylammonium chloride and ADBAC). For example any of thecomplexes of fatty acids:amino acids described herein may includeBenzalkonium chloride for use as a personal care product, such as, e.g.,hand sanitizers, wet wipes, shampoos, soaps, deodorants and cosmetics, adisinfectant (e.g., cleaner), a biocide (e.g., mouthwash, throatlozenge, etc.), a pharmaceutical agent (e.g., ear drop, eye drop, etc.),a burn or ulcer cream or agent, etc. For example, the compositionsdescribed herein may be a cleaning, disinfecting and/or sanitizingcomposition such as a cleaning wipe in which the composition isimpregnated, embedded, and/or saturated in/on the material forming thewipe (e.g., fabric, paper, polymer, etc.). Also described herein arecleaning compositions including a spray bottle or spray dispenser fordispensing the composition.

For example, in one variation, a solution including a complex of fattyacid:amino acid, such as a solution of GS-2 (Decanoic acid:Arginine) mayinclude Benzalkonium chloride at a final concentration of between about0.05% and about 5% (e.g., between about 0.05% and about 0.5%, betweenabout 0.1% and 0.5%, about 0.13%, about 0.4%, etc.), and may be used asa hand sanitizer, surface sanitizer, surface disinfectant or surfacecleaner. In some variations, the Decanoic acid may be between 0.1% and10% (e.g., between about 0.5% and about 5%, between about 1.0% and 5%,about 1.5%, etc.), and the Arginine (e.g., L-Arg) may be between about0.1% and 10% (e.g., between about 0.5% and about 5%, between about 1.0%and 5%, about 1.52%, etc.), in addition to the Benzalkonium chloride.This composition has been shown to be an effective sanitizing agent.Other complexes of fatty acid:amino acids as described herein (e.g.,GS-1, GS-3, GS-4, GS-5, GS-6, GS-7, GS-8, GS-9, GS-10, GS-11, GS-12,GS-13, etc.) may be used and have also been found (data not shown) to beeffective antibacterial/antiviral sanitizing agent, alone and incombination with a surfactant such as Benzalkonium chloride that doesnot disrupt the lamellar supramolecular structure as described herein.

Antimicrobial Coatings and Additives

As mentioned above, the compositions described herein may be used forcoatings and/or additives, including material additives e.g., to pain,plastics, etc.). For example, GS-1 was used to coat central venouscatheters to provide antimicrobial activity against gram-positive (MRSA)and gram-negative (E. coli) bacteria. In head-to-head testing, GS-1provided equivalent or better performance than chlorhexidine and silvercoatings already used in-market. Coatings may be applied by spraying,dipping, etc. The coatings may be encapsulated, partially encapsulatedand/or un-encapsulated.

A therapeutic composition as described herein may also be used as anadditive. For example, GS-1 was added to commercially availablewater-based paint at concentrations of 5% w/w, 10% w/w and 20% w/w toprovide antimicrobial activity. At all concentrations, the GS-1 additivesuccessfully eradicated gram-positive (MRSA) and gram-negative (E. coli)bacteria inoculated onto the surface within 24 hours. GS-1 was alsoadded to commercially available plastic (polyurethane) at concentrationsof 5% w/w and 10% w/w to provide antimicrobial properties. At bothconcentrations, the GS-1 additive successfully eradicated gram-positive(MRSA) and gram-negative (E. coli) bacteria inoculated onto the surfacewithin 24 hours.

The methods and compositions described herein may also be used fornon-medical/health applications, including for industrial use. Ingeneral, these methods and compositions may be used for any process orapplication in which an amino acid may be used to solubilize a fattyacid. Fatty acids are used for their carbon backbones in a wide range ofindustrial applications, such as for making nylon. A common problem inworking with fatty acids is that they are insoluble and liquid only athigh temperatures (thereby requiring lots of energy for heating). Themethods and compositions described herein, in which an amino acid, andparticularly an amino acid having an electrically charged basic sidechain (e.g., Lysine, Histidine, Arginine) may be used to solubilize thefatty acid (e.g., a C4-C40 fatty acid, a C4-C20 fatty acid, a C8-C20fatty acid, a C8-C18 fatty acid, etc.) in a molar ratio of between about1:0.6 to about 1:1.6, and may therefore be beneficial any time it isdesirable to have a fatty acid in solution.

Dose

In general, any appropriate dose may be used as part of a treatment asdescribed herein. Preliminary work suggests that the compositionsdescribed herein may be provided at a dose range that may be effectiveat very low concentrations (e.g., less than 0.1% w/w), but even higherconcentrations may be effective with little, if any side effects. Forexample, any of the methods described herein may be used to treat asubject within a range of between about 30% w/w and about 0.001% w/w. Insome variations the patient may be given a dose of between about 15% w/wand about 0.01% w/w. A patient may be treated with a dose of betweenabout 10% and about 0.01% w/w. A patient may be treated with a dose ofbetween about 5% and about 0.01% w/w. In some variations a patient maybe treated with a dose of between about 2.5% and about 0.01% w/w. Insome variations, the patient may be treated with a dose of between about1% and about 0.01% w/w. In some variations the patient may be treatedwith a dose of between about 0.5% and about 0.001% w/w. In somevariations, the patient may be treated with a dose of between about0.25% and about 0.001% w/w. In some variations, the patient may betreated with a dose of between about 0.25% and about 0.01% w/w.

More than one dose may be provided (e.g., 1× daily, 2× daily, 3× daily,4× daily, 5× daily, etc. 1 per 36 hours, 1 per 48 hours, 1 per 60 hours,1 per week, etc.).

Stability

In general, the therapeutic compositions described herein may include aratio of fatty acid (e.g., undecylenic acid) and amino acid (e.g.,L-Arginine) that is stable for storage. For example, compositions of UCAand LARG having a UCA to LARG molar ratio (UCA:LARG) of, e.g., betweenabout 1:0.6 to about 1:1.6 (and particularly about 1:0.65 to 1:1.4,e.g., about 1:0.65 to 1:1.3, about 1:0.65 to 1:1, etc.) may be stable attemperatures above 0 degrees C. for days, weeks or months. Further insome variations, the compositions described herein (e.g., compositionsof UCA and LARG) may be stable at even lower temperatures, particularlytemperatures such as −20 degrees C., for extended periods of time, e.g.,greater than 24 hours (greater than 2 days, 3 days, 4 days, 7 days, 10days, 14 days, 21 days, 30 days, 60 days, 120 days, 6 months, 1 year,etc.).

In particular, compositions of UCA and LARG having a molar ratio ofabout 1:1 (e.g. about 1:0.95 by weight) or about 5:4 (e.g., about 1:0.76by weight) may be especially stable over lower temperatures and longertimes. See, e.g., FIG. 19. In FIG. 19 (Table 3), the results of freezerstability (at −20 degrees C. for 24 hours) is shown, showing that thespecific molar ratios of UCA to LARG of 1:1 (e.g., 1:0.95 by weight) and5:4 (e.g., 1:0.76 by weight) exhibited superior stability at lowertemperatures as compared to other ratios of UCA:LARG. In FIG. 19, all ofthe compositions tested may be effective as anti-pathogen and/oranti-cancer compositions, and all of the compositions tested may bestable for extended periods when stored above freezing (e.g., >0 degreesC. for >24 hours), however the UCA:LARG at molar ratios of 1:1 and 5:4were exceptionally stable. In any of these examples, additionalstabilizing agents may be included to enhance stability.

Supramolecular Structure

A complex of fatty acid:amino acid including a C4-C40 (e.g., C8-C20,etc.) fatty acid and one or more of Arginine, Lysine and Histidine asdescribed herein may be formulated to form a lamellar (e.g.,multiple-layered) supramolecular structure, as illustrated in FIGS.40A-40C and 41, 42, 43A-43B, and 44A-44D.

The complexes of fatty acid:amino acid described herein mayself-assemble into specific supramolecular structures. This assembly maybe condition and/or concentration dependent. For example, at very lowconcentrations, one-dimensional (1D) “strings” of molecules may be firstformed. At higher concentrations, these 1D strings may assemble intotwo- or three-dimensional (2D or 3D) structures by wrapping together,creating multi-layered, lamellar, structures, like the layers of anonion. In some variations, these multi-layered structures may take theform of circular/spherical structures or “balls” (and in some variationsrod-like/ovoid structures). The multi-layered structures can also havehigher order assembly and interaction with adjacent multi-layeredstructures, especially as the concentration rises further. The lamellarstructures may be between 10 and 100 nm in diameter and may cluster(e.g., at higher concentration) together into clumps and branches.

For example, FIGS. 40A-40C illustrate the concentration-dependentformation of higher order supramolecular structures in GS-9. In FIG.40A, at a concentration of about 10 μg/mL of arachidonic acid (where themolar ratio of arachidonic acid:Lysine is approximately 1:1), small,e.g., 5-30 nm diameter, lamellar structures, spherical/rounded lamellarsupramolecular structures assemble. In FIG. 40B, at a higherconcentration (e.g., 100 μg/mL of arachidonic acid) the lamellarsupramolecular structures are enlarged (e.g., having an average diameterof between about 10-75 nm diameter), while in FIG. 40C, at aconcentration of about 1,000 μg/mL of arachidonic acid, the diameter isbetween 15-100 nm. Thus, as the concentration of L-lysine andarachidonic acid increases in water, the supramolecular structuresincrease in size and complexity. In FIG. 40C, the larger structuresclearly demonstrate progressive multi-lamellar layering that does notappear in lower concentrations.

The lamellar supramolecular structure may be functionally significant inachieving the therapeutic effects. Without being bound by theory, themulti-lamellar supramolecular structure may be significant fordisrupting bacteria and/or viruses. Further, the lamella supramolecularstructure may aid in packaging additional agents (and particularly thosethat may be otherwise insoluble or less soluble in water) in variationsincluding such agents.

Thus, in some variations it may be beneficial to select for complexes offatty acid:amino acid having lamellar supramolecular structures. Forexample, in some variations it may be beneficial to include therapeuticcompositions in which the complexes of fatty acid (e.g., C4-C40 fattyacid, C8-C20 fatty acid, etc.) amino acid (e.g., one or more ofArginine, Lysine, Histidine) form lamellar supramolecular structures.For example, the composition (e.g., the therapeutic composition) mayhave 10% or more of the complexes of fatty acid:amino acid as lamellarsupramolecular structures (e.g., 15% or more, 20% or more, 25% or more,30% or more, 35% or more, 40% or more 50% or more, 60% or more, 70% ormore, 75% or more, 80% or more, 90% or more, etc.).

FIG. 41 illustrates another example of the supramolecular structure of asolution including complexes of Arachidonic acid:Lysine (GS-9) in a 1:1ratio, similar to FIG. 40A-40C. In FIG. 41, the GS-9 is present with thearachidonic acid at 1 μg/mL. At this concentration, the complex forms‘string’ structures (arrows) that are believed to spontaneouslyassemble. Also present are layered (lamellar), rounded supramolecularstructures, increasingly present at higher concentrations. Although thesupramolecular structure of GS-9 is shown in FIGS. 40A-40C and 41, anyof the other therapeutic compositions described herein (e.g., GS-1,GS-2, GS-3, GS-4, etc.) are also believed to exhibit the samesupramolecular structures under equivalent conditions. It ishypothesized herein that the multi-layer (lamellar) supramolecularstructures may increase the charge density across the molecule, makingit more likely to engage with (and disrupt) bacterial and viralsurfaces.

FIG. 42 is a TEM micrograph showing examples of lamellar supramolecularstructures formed by complexes of GS-1 (undecylenic acid:LARG, in a 1:1molar ratio), showing multi-layered, three-dimensional nanoparticles inan aqueous solution. The lamellar structure looks similar or identicalto the GS-9 supramolecular structures described above.

Similar TEM images are shown in FIGS. 43A and 43B, and 44A-44D. In theseexamples, different magnifications of the GS-1 therapeutic compositionare shown, indicating a stable supramolecular structure.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Although the terms “first” and “second” may be used herein to describevarious features/elements (including steps), these features/elementsshould not be limited by these terms, unless the context indicatesotherwise. These terms may be used to distinguish one feature/elementfrom another feature/element. Thus, a first feature/element discussedbelow could be termed a second feature/element, and similarly, a secondfeature/element discussed below could be termed a first feature/elementwithout departing from the teachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co-jointlyemployed in the methods and articles (e.g., compositions and apparatusesincluding device and methods). For example, the term “comprising” willbe understood to imply the inclusion of any stated elements or steps butnot the exclusion of any other elements or steps.

In general, any of the apparatuses and methods described herein shouldbe understood to be inclusive, but all or a sub-set of the componentsand/or steps may alternatively be exclusive, and may be expressed as“consisting of” or alternatively “consisting essentially of” the variouscomponents, steps, sub-components or sub-steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical valuesgiven herein should also be understood to include about or approximatelythat value, unless the context indicates otherwise. For example, if thevalue “10” is disclosed, then “about 10” is also disclosed. Anynumerical range recited herein is intended to include all sub-rangessubsumed therein. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “X” is disclosed the “less than or equal to X” as well as “greaterthan or equal to X” (e.g., where X is a numerical value) is alsodisclosed. It is also understood that the throughout the application,data is provided in a number of different formats, and that this data,represents endpoints and starting points, and ranges for any combinationof the data points. For example, if a particular data point “10” and aparticular data point “15” are disclosed, it is understood that greaterthan, greater than or equal to, less than, less than or equal to, andequal to 10 and 15 are considered disclosed as well as between 10 and15. It is also understood that each unit between two particular unitsare also disclosed. For example, if 10 and 15 are disclosed, then 11,12, 13, and 14 are also disclosed.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description.

What is claimed is:
 1. A composition comprising, as a therapeuticcomplex, a mixture of undecylenic acid:Arginine forming a complex ofundecylenic acid and Arginine having a molar ratio of between 1:0.6 to1:1.6, wherein the composition is free of Rhein.
 2. The composition ofclaim 1, wherein the mixture of undecylenic acid:Arginine comprises amixture of undecylenic acid:L-Arginine.
 3. The composition of claim 1,wherein the composition comprises at least 0.001% w/w of the complex ofundecylenic acid and Arginine.
 4. The composition of claim 1, whereinthe molar ratio of undecylenic acid:Arginine is between 1:0.6 to 1:1.2.5. The composition of claim 1, wherein the molar ratio of undecylenicacid:Arginine is in a 1:1 molar ratio.
 6. The composition of claim 1,wherein the composition is free of cetyl alcohol.
 7. The composition ofclaim 1, wherein the composition is an aqueous composition.
 8. Thecomposition of claim 1, further comprising an excipient, diluent,carrier or fragrance.
 9. The composition of claim 8, wherein saidexcipient, diluent, carrier or fragrance is suitable for topicalapplication or for use on surfaces.
 10. The composition of claim 1,wherein the composition is configured as a liquid, emulsion, solution,ointment or cream in a form suitable for topical administration to ahuman or for use on surfaces.
 11. The composition of claim 1, whereinthe composition is configured for one or more of: oral, parenteral,intraperitoneal, transmucosal, transdermal, rectal, inhalable, andtopical administration.
 12. The composition of claim 1, wherein thecomposition is configured for administration as a hand sanitizer,surface sanitizer or disinfectant.
 13. The composition of claim 1,further comprising benzalkonium chloride.
 14. A composition comprisingan aqueous solution of a mixture of undecylenic acid: L-Arginine forminga therapeutic complex and having a molar ratio of undecylenic acid:L-Arginine of between 1:0.6 to 1:1.6 at a total concentration of atleast 0.001% w/w, wherein the composition is free of Rhein.
 15. Thecomposition of claim 14, wherein the molar ratio of undecylenic acid:L-Arginine is between 1:0.6 to 1:1.2.
 16. The composition of claim 14,wherein the molar ratio of undecylenic acid: L-Arginine is in a 1:1molar ratio.
 17. The composition of claim 14, further comprising anexcipient, diluent, carrier or fragrance.
 18. The composition of claim17, wherein said excipient, diluent, carrier or fragrance is suitablefor topical application or for use on surfaces.
 19. The composition ofclaim 14, wherein the composition is configured as a liquid, emulsion,solution, ointment or cream in a form suitable for topicaladministration to a human or for use on surfaces.
 20. The composition ofclaim 14, wherein the composition is configured for one or more of:oral, parenteral, intraperitoneal, transmucosal, transdermal, rectal,inhalable, and topical administration.
 21. The composition of claim 14,further comprising benzalkonium chloride.
 22. The composition of claim14, wherein the composition is configured for administration as a handsanitizer, surface sanitizer or disinfectant.
 23. A method of treating apatient for one or more of Staphylococcus aureus, Escherichia coli,Kebsiella pneumoniae, Pseudomonas aeruginosa, Herpes simplex viruses,Ebola, Human Rhinovirus-14, SARS Coronavirus, Dengue virus and YellowFever virus in need thereof, the method comprising: administering tosaid patient a therapeutically effective amount of a compositioncomprising an aqueous solution of a complex of undecylenic acid:L-Arginine in a molar ratio of between 1:0.6 to 1:1.6 wherein the totalconcentration of undecylenic acid: L-Arginine in the composition is atleast 0.001% w/w.
 24. The method of claim 23, wherein the molar ratio ofundecylenic acid: L-Arginine is in an approximately 1:1 molar ratio. 25.The method of claim 23, wherein administering comprises is applying thecomposition to the patient's skin.
 26. The method of claim 23, whereinthe patient has a cancer.
 27. The method of claim 26, wherein the canceris a skin cancer.
 28. A method of treating a patient for one or more ofglioma cell cancer, melanoma, leukemia, lung cancer, prostate cancer, orbreast cancer, the method comprising: administering to said patient atherapeutically effective amount of a composition comprising an aqueoussolution of a complex of undecylenic acid: L-Arginine in a molar ratioof between 1:0.6 to 1:1.6 wherein the total concentration of undecylenicacid: L-Arginine in the composition is at least 0.001% w/w.